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Review
LDL apheresis in Japan Hisashi Makino a , Tamiko Tamanaha a , Mariko Harada-Shiba b,∗ a b
Division of Atherosclerosis and Diabetes, National Cerebral and Cardiovascular Center, Japan Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, Japan
a r t i c l e
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Article history: Available online xxx Keywords: Familial hypercholesterolemia Atherosclerosis Peripheral artery disease
a b s t r a c t LDL apheresis has been developed as the treatment for refractory familial hypercholesterolemia (FH). Currently, plasma exchange, double membrane filtration, and selective LDL adsorption are available in Japan, and selective LDL adsorption is most common method. LDL apheresis can prevent atherosclerosis progression even in homozygous (HoFH). However, in our observational study, HoFH who started LDL apheresis from adulthood had poor prognosis compared with patients who started from childhood. Therefore, as far as possible, HoFH patients need to start LDL apheresis from childhood. Although indication of LDL apheresis in heterozygous FH (HeFH) has been decreasing with the advent of strong statin, our observational study showed that HeFH patients who were discontinued LDL apheresis therapy had poor prognosis compared with patients who were continued apheresis therapy. These results suggest that high risk HeFH need to be treated by LDL apheresis even if their LDLC is controlled by lipid-lowering agents. However, by launching new class of lipid lowering agents, that is, PCSK-9 antibody and MTP inhibitor, indication of LDL-apheresis in FH may be changed near the future. LDL-apheresis can provide symptom relief of peripheral artery disease (PAD). Therefore, PAD patients who have insufficient effect by other therapeutic approach including revascularization are also treated by LDL apheresis. Thus, LDL apheresis is still one of good therapeutic options for severe atherosclerotic diseases in Japan. © 2017 Published by Elsevier Ltd.
Contents 1. 2. 3.
4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Method of LDL apheresis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 LDL apheresis for atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.1. Mechanism of preventive effect on atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.2. LDL apheresis in FH. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .00 3.3. New lipid-lowering drugs and LDL apheresis in FH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.4. LDL apheresis in PAD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 LDL apheresis for renal disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1. Introduction Low density lipoprotein (LDL) apheresis, which depletes circulating LDL cholesterol (LDL-C) mechanically, has been developed
∗ Corresponding author at: Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. E-mail address: [email protected] (M. Harada-Shiba).
as the treatment for refractory familial hypercholesterolemia (FH) patients. FH is autosomal dominant disorder caused by a mutation in the gene encoding the LDL receptor. Patients homozygous for FH have severe hypercholesterolemia (600–1000 mg/dL), cutaneous and tendon xanthomas, and premature atherosclerosis [1]. The development of HMG-CoA reductase inhibitors (statin) has enabled effective treatment for most of heterozygous (HeFH) [2]. Indeed, the average age at coronary artery disease (CAD) onset was significantly higher after widespread use of statins compared to before October 1989 when statins were approved in Japan [3].
http://dx.doi.org/10.1016/j.transci.2017.08.014 1473-0502/© 2017 Published by Elsevier Ltd.
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However, patients homozygous (HoFH) are resistant to these drugs because statins reduce LDLC levels mostly via an increase in the number of LDL receptors in the liver. Therefore, LDL apheresis is the only practical method to control LDL levels in patients homozygous for FH and in some other types of severe hypercholesterolemia such as autosomal recessive hypercholesterolemia. LDL apheresis is also effective for other disease such as peripheral artery disease (PAD) and focal segmental glomerular sclerosis (FSGS), a glomerular disease which causes refractory nephrotic syndrome. Therefore, LDL apheresis for these diseases is also covered by health insurance in Japan. Currently, plasma exchange, double filtration plasmapheresis, and LDL selective adsorption, are available as LDL apheresis therapy in Japan. Among them, LDL selective absorption is most popular method. 2. Method of LDL apheresis The first trial of LDL apheresis in HoFH patients was performed as plasma exchange by DeGenne et al. in 1967 [4]. This therapeutic approach provided improvement of coronary artery stenosis, withdrawal of xanthoma accompanied with LDLC reduction. However, plasma exchange has disadvantage that various important substances such as immunoglobulin are removed along with LDLC. Therefore, today, plasma exchange is only used for FH patients aged 10 years who cannot be treated with LDL absorption because of small capacity of extracorporeal circulation. The double membrane filtration (DFPP) and LDL selective adsorption are now widely used in Japan. The advantage of DFPP is the selective removal of macromolecules based on molecular weight and filter pore size. Initially, treatable plasma volume was limited in this procedure because of the increase in the membrane pressure. An improvement of the sieving properties, however, has enabled us to treat a larger plasma volume. In 1980s, dextran sulfate-coated cellulose beads was proved a potent specific sorbent of apolipoprotein B-containing lipoproteins [5]. The early system of LDL absorption (LA-40 system) had large column (400 ml) using this sorbent. However, this system could not remove LDLC adequately, since the column was saturated if treated plasma volume was large. Currently, LDL-adsorption system (LA-15 system, Kaneka, Osaka, Japan) has two small columns whose volume is 150 ml. Each column is alternately reused during apheresis therapy by eluting adsorbed LDL on saturated column by 5% NaCl. This current system can treat large volume of plasma and reduce cardiovascular burden during apheresis therapy. Therefore, this system can be available for patients with cardiac dysfunction or small body mass, and today, LA-15 system is widely used all over the world. LDL absorption system promotes the production of bradykinin by activation of coagulation system since adsorption column has negative charge [6]. Therefore, it is important to note that patients who were received angiotensin converting enzyme inhibitor must not be treated with this system. 3. LDL apheresis for atherosclerosis 3.1. Mechanism of preventive effect on atherosclerosis LDL adsorption therapy can remove not only LDL-C but also cell adhesion molecule such as intracellular adhesion molecule-1 and vascular cell adhesion molecule [7,8], fibrinolytic factor such as fibrinogen and plasminogen activator inhibitor-1 [9]. LDL adsorption also can remove inflammatory cytokine such as tumor necrosis factor-␣ and interleukin-1 [10], and reduce reactive oxygen species production via suppression of NAPDH oxidase [11]. These factors play a key role in the progression of atherosclerosis. Thus LDL adsorption can prevent atherosclerosis dependent and indepenPlease cite this article in press as: Makino http://dx.doi.org/10.1016/j.transci.2017.08.014
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dent of LDLC removal. LDL adsorption therapy was also reported to improve vascular endothelial function via induction of bradykinin and nitric oxide production [12]. LDL apheresis also improves atherogenic lipid metabolism in addition to direct removal of LDLC. In patients of peripheral artery disease, oxidized LDL was removed by LDL adsorption and removal rate of oxidized LDL was associated with the improvement of walk distance [13]. We also found that small dense LDL-C which has strong atherogenic action was efficiently removed by LDL apheresis in FH patients. Furthermore, we reported that LDL apheresis could remove ApoC3 [14] which is an endogenous lipoprotein lipase inhibitor and promote atherosclerosis progression [15]. LDL adsorption could remove proprotein convertase subtilisin/kexin type 9 (PCSK9) [16,17]. PCSK9 play a pivotal role in lipid metabolism by enhancing endosomal and lysosomal degradation of LDL receptor in the liver [18]. In addition, PCSK9 is involved in inflammatory process by upregulating proinflammatory gene expression [19]. Thus, LDL adsorption has various anti-atherosclerotic effect as well as LDL-C removal. 3.2. LDL apheresis in FH HoFH patients usually are started with LDL apheresis therapy at about 10 years old. Before LDL adsorption therapy, they are treated with plasma exchange therapy if possible. We investigated the long term effect of LDL apheresis in 8 patients with HoFH (observation period was 3–20 years.) (Table 1) [20]. Five patients started to be treated with LDL apheresis from childhood. Among these five patients, one was free from atherosclerotic disease, one revealed remission of atherosclerosis. Other three patients had supravalvular aortic stenosis or coronary artery stenosis, but atherosclerotic diseases in these three patients were relatively mild. On the other hand, three patients who started to be treated LDL apheresis from adult had severe atherosclerosis. Two of these three patients died from myocardial infarction, and one was carried out coronary artery bypass before initiation of LDL apheresis. Græsdal et al. also reported that patients who received LDL apheresis therapy from 10 years old revealed mild atherosclerotic change whereas two patients who started LDL apheresis at adult already had coronary artery disease before LDL apheresis initiation [21]. Thus, LDL apheresis should be initiated as early as possible in HoFH to prevent atherosclerotic disease progression. Although there is no international guideline of target LDLC level of LDL apheresis therapy, generally, LDL-apheresis is performed every 1–2 weeks, and LDL-C level after LDL apheresis is below 50 mg/dL in Japan. Previously, some FH patients withdrew LDL apheresis for the financial burden even though they needed this therapy. After 2009, medical expense of Ho-FH is covered by publicly funded health care in Japan. Moreover, there are many medical setting which can perform LDL apheresis in Japan. Therefore, currently, Japanese Ho-FH patients can appropriately receive LDL apheresis. There are increased stresses on the cardiovascular system throughout pregnancy and delivery. Both blood volume and cardiac output increase by 25–80% [22]. The main point of concern has been the aggravation of coronary insufficiency of the mother, mainly due to these hemodynamic changes in pregnancy [23]. Therefore, during pregnancy, HoFH and HeFH with severe coronary artery disease should be treated by LDL apheresis to prevent further progression of coronary atherosclerosis and to tolerate the increased stress of delivery. In fact, our recent report of 7 FH patients with pregnancy showed that a patient who refused LDL apheresis during pregnancy and another patient whose adherence of LDL apheresis was poor died from acute myocardial infarction [24]. High lipid levels may also affect placental vasculature and cause retardation of fatal growth [25]. Therefore, in Japan, HoFH and HeFH with severe coronary artery disease are treated by LDL apheresis during the course of LDL
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Table 1 Clinical characteristics of patients with homozygous familial hyperlipidemia (Ref. [20]). Patient no
Age span during low density lipoprotein apheresis treatment
Cardiovascular findings
1 (F)
4–19 years-old
2 (M)
6–13 years-old
3 (F)
9–12 years-old
4 (F)
6–24 years-old
5 (M)
12–27 years-old
6 (F) 7 (M) 8 (F)
12–40 years-old 27–29 years 25–32 years
Coronary artery stenosis has not occurred. Aortic wall is smooth and valve is normal. At 5 years, coronary artery and aorta were almost normal. At 12 years, thickening of the aortic wall and supravalvular stenosis (pressure gradient 70 mmHg). At 10 years, coronary artery stenosis was not observed. At 27 years, 100% stenosis of right coronary artery was apparent. Obstraction of left main trunk was found at age 6. The aortocoronary bypass surgery was carried out at age 10 and 15. 50% stenosis of graft was observed at age 24. Aortic wall became smoother once, but aortic regurgitation worsened. Aortocoronary bypass was carried out at 18 years. At 29 years, patient died of acute myocardial infarction. At 31 years, patient had aortic valve stenosis and intact coronary artery. Patient died of myocardial infarction at age of 32.
pregnancy to control their cholesterol level not only for their own sake but also for normal fatal growth. In any case, pregnancy and delivery in women with ischemic heart disease is hazardous and should be monitored very closely. Further, we should pay attention to the symptoms due to bradykinin overproduction such as nausea, bradycardia, and hypotension [24]. LDL-apheresis is also covered health insurance to HeFH whose TC gg>250 mg/dL in spite of lipid-lowering drugs and Ht-FH with severe cardiovascular disease. There are several evidences of usefulness of LDL apheresis for prevention of atherosclerosis progression of HeFH. LDL-apheresis atherosclerosis regression study (LAARS) demonstrated that LDL apheresis significantly prevented coronary artery disease progression compared with only medication [26]. The progression of coronary artery disease was well prevented especially in case of LDLC level reduced to 100 mg/dL before apheresis, although mean LDLC level before apheresis was 249 mg/dL and mean LDLC level after apheresis was 105 mg/dL in LAARS [26]. Mabuchi et al. also reported that incidence of CVD in HeFH patients who received LDL apheresis was occurred less frequently than patients who received only medication therapy in Hokuriku-FH-LDL-Apheresis Study [27]. Furthermore, LDL apheresis therapy could induce regression of atherosclerotic plaque of coronary artery LDL apheresis in HeFH (Low Density LipoproteinApheresis Coronary Morphology and Reserve Trial) [28]. In our observational study, HeFH patients who were discontinued LDL apheresis therapy had poor prognosis compared with patients who were continued apheresis therapy (Fig. 1), although patients who discontinued LDL apheresis had almost same level of LDLC compared with patients who continued LDL apheresis [29]. Therefore, it is indicated that some HeFH patients with severe atherosclerotic disease still require LDL apheresis therapy although lipid lowering drugs are developed. 3.3. New lipid-lowering drugs and LDL apheresis in FH In 2016, a PCSK9 antibody, evolocumab was approved in Japan. A recent clinical trial demonstrated that 50–60% reduction of LDL-C was achieved by evolocumab in FH [30]. Therefore, number of FH patients treated by LDL apheresis is decreasing, since FH patients can withdraw by induction of PCSK9 antibody. Recently, microsomal triglyceride transfer protein (MTP) inhibitor, which inhibit VLDL synthesis in liver [31], was approved in Japan. This agent can reduce LDL-C even in Ho-FH, although it almost always causes diarrhea and liver dysfunction. Therefore, Please cite this article in press as: Makino http://dx.doi.org/10.1016/j.transci.2017.08.014
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Fig. 1. Comparison of prognosis of HeFH between LDL apheresis continuation group and LDL apheresis withdrawal group (Ref. [29]).
it is expected that frequency of LDL apheresis may decrease by induction of MTP inhibitor. 3.4. LDL apheresis in PAD In Japan, indicated usage of LDL apheresis for the treatment of PAD under the government system of insurance coverage, includes the following: (i) clinical signs of poor peripheral circulation, such as cold, decolored or ulcerated extremities, or intermittent claudication consistent with a Fontaine classification of Grade II or more; (ii) refractoriness to conventional medical or surgical treatment; (iii) an excessively high LDL-C or TC levels (LDL-C >140 mg/dL or TC >220 mg/dL) in spite of drug treatment [32]. Generally, for treatment of PAD, LDL apheresis is performed once a week for 10 weeks, and treating 2000–5000 ml of plasma for each session. Several reports showed efficacy of LDL apheresis on PAD. Peripheral arterial disease LDL apheresis multicenter study showed that LDL adsorption improved ankle brachial index (ABI) and maximum tolerated walking distance [33]. Other report showed that the improvement of resting leg pain in PAD patients undergoing hemodialysis maintained at least 4 weeks after final apheresis probably by improvement of vascular endothelial function in addition to lipid reduction [34]. Thus LDL apheresis is good treatment option for PAD in case revascularization is impossible and medical manLDL
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agement is not able to improve the symptom. In Japan, most PAD patients treated by LDL apheresis are end-stage kidney disease patients with hemodialysis since they do not hesitate extracorporeal circulation and are absent from economical burden. However, characteristics of suitable PAD patients for LDL apheresis have been still unclear. 4. LDL apheresis for renal disease LDL apheresis is reported to be effective for refractory nephrotic syndrome due to FSGS. Refractory nephrotic syndrome persist dyslipidemia, which exacerbates not only progression of atherosclerosis but also damages of glomeruli and renal tubules [35]. Therefore, correction of dyslipidemia is important for the treatment of refractory nephrotic syndrome. LDL apheresis also can prevent progression of FSGS through enhance response to immunosuppressant by amelioration of intracellular drug transport, removal of inflammatory cytokine, and removal of humoral factors responsible for nephrotic syndrome [36]. In Japan, LDL apheresis to FSGS is covered by health insurance. Generally, LDL apheresis is carried out 12 times during 3 months. A Japanese prospective observational study, PORALIS study showed that 21 of 44 (47.7%) patients of refractory nephrotic syndrome showed remission based on a urinary protein level 1.0 g/day by LDL apheresis [37]. LDL apheresis is sometimes performed to cholesterol embolism in Japan. A previous case report showed that LDL apheresis improved blue toe, pain, and livedo reticularis in cholesterol embolism [38]. 5. Conclusion Number of HeFH who should be treated with LDL apheresis has been decreasing because of therapeutic advance of lipid lowering agent, although HoFH must be treated with LDL apheresis. Furthermore, novel lipid lowering agent such as PCSK9 antibody and MTP inhibitor is now available in Japan. Therefore, number of patients who should be treated with LDL apheresis and frequency of LDL apheresis on each patient may further decrease even in HoFH. However, LDL adsorption can strongly remove not only atherosclerotic lipoproteins but also other atherogenic factors. Therefore, LDL apheresis is still important therapeutic option for FH patients with severe atherosclerosis. References [1] Goldstein JL, Brown MS. The metabolic basis of inherited disease. 5th ed. New York: McGraw-Hill; 1982. [2] Illingworth R. How effective is drug therapy in heterozygous familial hypercholesterolemia. Am J Cardiol 1993;72:D54–8. [3] Harada-Shiba M, Sugisawa T, Makino H, Abe M, Tsushima M, Yoshimasa Y, et al. Impact of statin treatment on the clinical fate of heterozygous familial hypercholesterolemia. J Atheroscler Thromb 2010;17:667–74. [4] de Gennes JL, Touraine R, Maunand B. Homozygous cutaneo-tendinous forms of hypercholesteremic xanthomatosis in an exemplary familial case. Trial of plasmapheresis and heroic treatment. Bull Mem Soc Med Hop Paris 1967;118:1377–402. [5] Yokoyama S, Hayashi R, Kikkawa T, Tani N, Takada S, Hatanaka K, et al. Specific sorbent of apolipoprotein B-containing lipoproteins for plasmapheresis. Characterization and experimental use in hypercholesterolemic rabbits. Arteriosclerosis 1984;4:276–82. [6] Krieter DH, Steinke J, Kerkhoff M, Fink E, Lemke HD, Zingler C, et al. Contact activation in low-density lipoprotein apheresis systems. Artif Organs 2005;29:47–52. [7] Sampietro T, Tuoni M, Ferdeghini M, Ciardi A, Marraccini P, Prontera C, et al. Plasma cholesterol regulates soluble cell adhesion molecule expression in familial hypercholesterolemia. Circulation 1997;96:1381–5. [8] Utsumi K, Kawabe M, Hirama A, Ueda K, Kamada Y, Arii K, et al. Effects of selective LDL apheresis on plasma concentrations of ICAM-1, VCAM-1 and P-selectin in diabetic patients with arteriosclerosis obliterans and receiving maintenance hemodialysis. Clin Chim Acta 2007;377:198–200.
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[37] Muso E, Mune M, Hirano T, Hattori M, Kimura K, Watanabe T, et al. A prospective observational survey on the long-term effect of LDL apheresis on drug-resistant nephrotic syndrome. Nephron Extra 2015;5:58–66. [38] Tsunoda S, Daimon S, Miyazaki R, Fujii H, Inazu A, Mabuchi H. LDL apheresis as intensive lipid-lowering therapy for cholesterol embolism. Nephrol Dial Transplant 1999;14:1041–2.
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Review
LDL apheresis in Japan Hisashi Makino a , Tamiko Tamanaha a , Mariko Harada-Shiba b,∗ a b
Division of Atherosclerosis and Diabetes, National Cerebral and Cardiovascular Center, Japan Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, Japan
a r t i c l e
i n f o
Article history: Available online xxx Keywords: Familial hypercholesterolemia Atherosclerosis Peripheral artery disease
a b s t r a c t LDL apheresis has been developed as the treatment for refractory familial hypercholesterolemia (FH). Currently, plasma exchange, double membrane filtration, and selective LDL adsorption are available in Japan, and selective LDL adsorption is most common method. LDL apheresis can prevent atherosclerosis progression even in homozygous (HoFH). However, in our observational study, HoFH who started LDL apheresis from adulthood had poor prognosis compared with patients who started from childhood. Therefore, as far as possible, HoFH patients need to start LDL apheresis from childhood. Although indication of LDL apheresis in heterozygous FH (HeFH) has been decreasing with the advent of strong statin, our observational study showed that HeFH patients who were discontinued LDL apheresis therapy had poor prognosis compared with patients who were continued apheresis therapy. These results suggest that high risk HeFH need to be treated by LDL apheresis even if their LDLC is controlled by lipid-lowering agents. However, by launching new class of lipid lowering agents, that is, PCSK-9 antibody and MTP inhibitor, indication of LDL-apheresis in FH may be changed near the future. LDL-apheresis can provide symptom relief of peripheral artery disease (PAD). Therefore, PAD patients who have insufficient effect by other therapeutic approach including revascularization are also treated by LDL apheresis. Thus, LDL apheresis is still one of good therapeutic options for severe atherosclerotic diseases in Japan. © 2017 Published by Elsevier Ltd.
Contents 1. 2. 3.
4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Method of LDL apheresis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 LDL apheresis for atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.1. Mechanism of preventive effect on atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.2. LDL apheresis in FH. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .00 3.3. New lipid-lowering drugs and LDL apheresis in FH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.4. LDL apheresis in PAD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 LDL apheresis for renal disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1. Introduction Low density lipoprotein (LDL) apheresis, which depletes circulating LDL cholesterol (LDL-C) mechanically, has been developed
∗ Corresponding author at: Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. E-mail address: [email protected] (M. Harada-Shiba).
as the treatment for refractory familial hypercholesterolemia (FH) patients. FH is autosomal dominant disorder caused by a mutation in the gene encoding the LDL receptor. Patients homozygous for FH have severe hypercholesterolemia (600–1000 mg/dL), cutaneous and tendon xanthomas, and premature atherosclerosis [1]. The development of HMG-CoA reductase inhibitors (statin) has enabled effective treatment for most of heterozygous (HeFH) [2]. Indeed, the average age at coronary artery disease (CAD) onset was significantly higher after widespread use of statins compared to before October 1989 when statins were approved in Japan [3].
http://dx.doi.org/10.1016/j.transci.2017.08.014 1473-0502/© 2017 Published by Elsevier Ltd.
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However, patients homozygous (HoFH) are resistant to these drugs because statins reduce LDLC levels mostly via an increase in the number of LDL receptors in the liver. Therefore, LDL apheresis is the only practical method to control LDL levels in patients homozygous for FH and in some other types of severe hypercholesterolemia such as autosomal recessive hypercholesterolemia. LDL apheresis is also effective for other disease such as peripheral artery disease (PAD) and focal segmental glomerular sclerosis (FSGS), a glomerular disease which causes refractory nephrotic syndrome. Therefore, LDL apheresis for these diseases is also covered by health insurance in Japan. Currently, plasma exchange, double filtration plasmapheresis, and LDL selective adsorption, are available as LDL apheresis therapy in Japan. Among them, LDL selective absorption is most popular method. 2. Method of LDL apheresis The first trial of LDL apheresis in HoFH patients was performed as plasma exchange by DeGenne et al. in 1967 [4]. This therapeutic approach provided improvement of coronary artery stenosis, withdrawal of xanthoma accompanied with LDLC reduction. However, plasma exchange has disadvantage that various important substances such as immunoglobulin are removed along with LDLC. Therefore, today, plasma exchange is only used for FH patients aged 10 years who cannot be treated with LDL absorption because of small capacity of extracorporeal circulation. The double membrane filtration (DFPP) and LDL selective adsorption are now widely used in Japan. The advantage of DFPP is the selective removal of macromolecules based on molecular weight and filter pore size. Initially, treatable plasma volume was limited in this procedure because of the increase in the membrane pressure. An improvement of the sieving properties, however, has enabled us to treat a larger plasma volume. In 1980s, dextran sulfate-coated cellulose beads was proved a potent specific sorbent of apolipoprotein B-containing lipoproteins [5]. The early system of LDL absorption (LA-40 system) had large column (400 ml) using this sorbent. However, this system could not remove LDLC adequately, since the column was saturated if treated plasma volume was large. Currently, LDL-adsorption system (LA-15 system, Kaneka, Osaka, Japan) has two small columns whose volume is 150 ml. Each column is alternately reused during apheresis therapy by eluting adsorbed LDL on saturated column by 5% NaCl. This current system can treat large volume of plasma and reduce cardiovascular burden during apheresis therapy. Therefore, this system can be available for patients with cardiac dysfunction or small body mass, and today, LA-15 system is widely used all over the world. LDL absorption system promotes the production of bradykinin by activation of coagulation system since adsorption column has negative charge [6]. Therefore, it is important to note that patients who were received angiotensin converting enzyme inhibitor must not be treated with this system. 3. LDL apheresis for atherosclerosis 3.1. Mechanism of preventive effect on atherosclerosis LDL adsorption therapy can remove not only LDL-C but also cell adhesion molecule such as intracellular adhesion molecule-1 and vascular cell adhesion molecule [7,8], fibrinolytic factor such as fibrinogen and plasminogen activator inhibitor-1 [9]. LDL adsorption also can remove inflammatory cytokine such as tumor necrosis factor-␣ and interleukin-1 [10], and reduce reactive oxygen species production via suppression of NAPDH oxidase [11]. These factors play a key role in the progression of atherosclerosis. Thus LDL adsorption can prevent atherosclerosis dependent and indepenPlease cite this article in press as: Makino http://dx.doi.org/10.1016/j.transci.2017.08.014
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dent of LDLC removal. LDL adsorption therapy was also reported to improve vascular endothelial function via induction of bradykinin and nitric oxide production [12]. LDL apheresis also improves atherogenic lipid metabolism in addition to direct removal of LDLC. In patients of peripheral artery disease, oxidized LDL was removed by LDL adsorption and removal rate of oxidized LDL was associated with the improvement of walk distance [13]. We also found that small dense LDL-C which has strong atherogenic action was efficiently removed by LDL apheresis in FH patients. Furthermore, we reported that LDL apheresis could remove ApoC3 [14] which is an endogenous lipoprotein lipase inhibitor and promote atherosclerosis progression [15]. LDL adsorption could remove proprotein convertase subtilisin/kexin type 9 (PCSK9) [16,17]. PCSK9 play a pivotal role in lipid metabolism by enhancing endosomal and lysosomal degradation of LDL receptor in the liver [18]. In addition, PCSK9 is involved in inflammatory process by upregulating proinflammatory gene expression [19]. Thus, LDL adsorption has various anti-atherosclerotic effect as well as LDL-C removal. 3.2. LDL apheresis in FH HoFH patients usually are started with LDL apheresis therapy at about 10 years old. Before LDL adsorption therapy, they are treated with plasma exchange therapy if possible. We investigated the long term effect of LDL apheresis in 8 patients with HoFH (observation period was 3–20 years.) (Table 1) [20]. Five patients started to be treated with LDL apheresis from childhood. Among these five patients, one was free from atherosclerotic disease, one revealed remission of atherosclerosis. Other three patients had supravalvular aortic stenosis or coronary artery stenosis, but atherosclerotic diseases in these three patients were relatively mild. On the other hand, three patients who started to be treated LDL apheresis from adult had severe atherosclerosis. Two of these three patients died from myocardial infarction, and one was carried out coronary artery bypass before initiation of LDL apheresis. Græsdal et al. also reported that patients who received LDL apheresis therapy from 10 years old revealed mild atherosclerotic change whereas two patients who started LDL apheresis at adult already had coronary artery disease before LDL apheresis initiation [21]. Thus, LDL apheresis should be initiated as early as possible in HoFH to prevent atherosclerotic disease progression. Although there is no international guideline of target LDLC level of LDL apheresis therapy, generally, LDL-apheresis is performed every 1–2 weeks, and LDL-C level after LDL apheresis is below 50 mg/dL in Japan. Previously, some FH patients withdrew LDL apheresis for the financial burden even though they needed this therapy. After 2009, medical expense of Ho-FH is covered by publicly funded health care in Japan. Moreover, there are many medical setting which can perform LDL apheresis in Japan. Therefore, currently, Japanese Ho-FH patients can appropriately receive LDL apheresis. There are increased stresses on the cardiovascular system throughout pregnancy and delivery. Both blood volume and cardiac output increase by 25–80% [22]. The main point of concern has been the aggravation of coronary insufficiency of the mother, mainly due to these hemodynamic changes in pregnancy [23]. Therefore, during pregnancy, HoFH and HeFH with severe coronary artery disease should be treated by LDL apheresis to prevent further progression of coronary atherosclerosis and to tolerate the increased stress of delivery. In fact, our recent report of 7 FH patients with pregnancy showed that a patient who refused LDL apheresis during pregnancy and another patient whose adherence of LDL apheresis was poor died from acute myocardial infarction [24]. High lipid levels may also affect placental vasculature and cause retardation of fatal growth [25]. Therefore, in Japan, HoFH and HeFH with severe coronary artery disease are treated by LDL apheresis during the course of LDL
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Table 1 Clinical characteristics of patients with homozygous familial hyperlipidemia (Ref. [20]). Patient no
Age span during low density lipoprotein apheresis treatment
Cardiovascular findings
1 (F)
4–19 years-old
2 (M)
6–13 years-old
3 (F)
9–12 years-old
4 (F)
6–24 years-old
5 (M)
12–27 years-old
6 (F) 7 (M) 8 (F)
12–40 years-old 27–29 years 25–32 years
Coronary artery stenosis has not occurred. Aortic wall is smooth and valve is normal. At 5 years, coronary artery and aorta were almost normal. At 12 years, thickening of the aortic wall and supravalvular stenosis (pressure gradient 70 mmHg). At 10 years, coronary artery stenosis was not observed. At 27 years, 100% stenosis of right coronary artery was apparent. Obstraction of left main trunk was found at age 6. The aortocoronary bypass surgery was carried out at age 10 and 15. 50% stenosis of graft was observed at age 24. Aortic wall became smoother once, but aortic regurgitation worsened. Aortocoronary bypass was carried out at 18 years. At 29 years, patient died of acute myocardial infarction. At 31 years, patient had aortic valve stenosis and intact coronary artery. Patient died of myocardial infarction at age of 32.
pregnancy to control their cholesterol level not only for their own sake but also for normal fatal growth. In any case, pregnancy and delivery in women with ischemic heart disease is hazardous and should be monitored very closely. Further, we should pay attention to the symptoms due to bradykinin overproduction such as nausea, bradycardia, and hypotension [24]. LDL-apheresis is also covered health insurance to HeFH whose TC gg>250 mg/dL in spite of lipid-lowering drugs and Ht-FH with severe cardiovascular disease. There are several evidences of usefulness of LDL apheresis for prevention of atherosclerosis progression of HeFH. LDL-apheresis atherosclerosis regression study (LAARS) demonstrated that LDL apheresis significantly prevented coronary artery disease progression compared with only medication [26]. The progression of coronary artery disease was well prevented especially in case of LDLC level reduced to 100 mg/dL before apheresis, although mean LDLC level before apheresis was 249 mg/dL and mean LDLC level after apheresis was 105 mg/dL in LAARS [26]. Mabuchi et al. also reported that incidence of CVD in HeFH patients who received LDL apheresis was occurred less frequently than patients who received only medication therapy in Hokuriku-FH-LDL-Apheresis Study [27]. Furthermore, LDL apheresis therapy could induce regression of atherosclerotic plaque of coronary artery LDL apheresis in HeFH (Low Density LipoproteinApheresis Coronary Morphology and Reserve Trial) [28]. In our observational study, HeFH patients who were discontinued LDL apheresis therapy had poor prognosis compared with patients who were continued apheresis therapy (Fig. 1), although patients who discontinued LDL apheresis had almost same level of LDLC compared with patients who continued LDL apheresis [29]. Therefore, it is indicated that some HeFH patients with severe atherosclerotic disease still require LDL apheresis therapy although lipid lowering drugs are developed. 3.3. New lipid-lowering drugs and LDL apheresis in FH In 2016, a PCSK9 antibody, evolocumab was approved in Japan. A recent clinical trial demonstrated that 50–60% reduction of LDL-C was achieved by evolocumab in FH [30]. Therefore, number of FH patients treated by LDL apheresis is decreasing, since FH patients can withdraw by induction of PCSK9 antibody. Recently, microsomal triglyceride transfer protein (MTP) inhibitor, which inhibit VLDL synthesis in liver [31], was approved in Japan. This agent can reduce LDL-C even in Ho-FH, although it almost always causes diarrhea and liver dysfunction. Therefore, Please cite this article in press as: Makino http://dx.doi.org/10.1016/j.transci.2017.08.014
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Fig. 1. Comparison of prognosis of HeFH between LDL apheresis continuation group and LDL apheresis withdrawal group (Ref. [29]).
it is expected that frequency of LDL apheresis may decrease by induction of MTP inhibitor. 3.4. LDL apheresis in PAD In Japan, indicated usage of LDL apheresis for the treatment of PAD under the government system of insurance coverage, includes the following: (i) clinical signs of poor peripheral circulation, such as cold, decolored or ulcerated extremities, or intermittent claudication consistent with a Fontaine classification of Grade II or more; (ii) refractoriness to conventional medical or surgical treatment; (iii) an excessively high LDL-C or TC levels (LDL-C >140 mg/dL or TC >220 mg/dL) in spite of drug treatment [32]. Generally, for treatment of PAD, LDL apheresis is performed once a week for 10 weeks, and treating 2000–5000 ml of plasma for each session. Several reports showed efficacy of LDL apheresis on PAD. Peripheral arterial disease LDL apheresis multicenter study showed that LDL adsorption improved ankle brachial index (ABI) and maximum tolerated walking distance [33]. Other report showed that the improvement of resting leg pain in PAD patients undergoing hemodialysis maintained at least 4 weeks after final apheresis probably by improvement of vascular endothelial function in addition to lipid reduction [34]. Thus LDL apheresis is good treatment option for PAD in case revascularization is impossible and medical manLDL
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agement is not able to improve the symptom. In Japan, most PAD patients treated by LDL apheresis are end-stage kidney disease patients with hemodialysis since they do not hesitate extracorporeal circulation and are absent from economical burden. However, characteristics of suitable PAD patients for LDL apheresis have been still unclear. 4. LDL apheresis for renal disease LDL apheresis is reported to be effective for refractory nephrotic syndrome due to FSGS. Refractory nephrotic syndrome persist dyslipidemia, which exacerbates not only progression of atherosclerosis but also damages of glomeruli and renal tubules [35]. Therefore, correction of dyslipidemia is important for the treatment of refractory nephrotic syndrome. LDL apheresis also can prevent progression of FSGS through enhance response to immunosuppressant by amelioration of intracellular drug transport, removal of inflammatory cytokine, and removal of humoral factors responsible for nephrotic syndrome [36]. In Japan, LDL apheresis to FSGS is covered by health insurance. Generally, LDL apheresis is carried out 12 times during 3 months. A Japanese prospective observational study, PORALIS study showed that 21 of 44 (47.7%) patients of refractory nephrotic syndrome showed remission based on a urinary protein level 1.0 g/day by LDL apheresis [37]. LDL apheresis is sometimes performed to cholesterol embolism in Japan. A previous case report showed that LDL apheresis improved blue toe, pain, and livedo reticularis in cholesterol embolism [38]. 5. Conclusion Number of HeFH who should be treated with LDL apheresis has been decreasing because of therapeutic advance of lipid lowering agent, although HoFH must be treated with LDL apheresis. Furthermore, novel lipid lowering agent such as PCSK9 antibody and MTP inhibitor is now available in Japan. Therefore, number of patients who should be treated with LDL apheresis and frequency of LDL apheresis on each patient may further decrease even in HoFH. However, LDL adsorption can strongly remove not only atherosclerotic lipoproteins but also other atherogenic factors. Therefore, LDL apheresis is still important therapeutic option for FH patients with severe atherosclerosis. References [1] Goldstein JL, Brown MS. The metabolic basis of inherited disease. 5th ed. New York: McGraw-Hill; 1982. [2] Illingworth R. How effective is drug therapy in heterozygous familial hypercholesterolemia. Am J Cardiol 1993;72:D54–8. [3] Harada-Shiba M, Sugisawa T, Makino H, Abe M, Tsushima M, Yoshimasa Y, et al. Impact of statin treatment on the clinical fate of heterozygous familial hypercholesterolemia. J Atheroscler Thromb 2010;17:667–74. [4] de Gennes JL, Touraine R, Maunand B. Homozygous cutaneo-tendinous forms of hypercholesteremic xanthomatosis in an exemplary familial case. Trial of plasmapheresis and heroic treatment. Bull Mem Soc Med Hop Paris 1967;118:1377–402. [5] Yokoyama S, Hayashi R, Kikkawa T, Tani N, Takada S, Hatanaka K, et al. Specific sorbent of apolipoprotein B-containing lipoproteins for plasmapheresis. Characterization and experimental use in hypercholesterolemic rabbits. Arteriosclerosis 1984;4:276–82. [6] Krieter DH, Steinke J, Kerkhoff M, Fink E, Lemke HD, Zingler C, et al. Contact activation in low-density lipoprotein apheresis systems. Artif Organs 2005;29:47–52. [7] Sampietro T, Tuoni M, Ferdeghini M, Ciardi A, Marraccini P, Prontera C, et al. Plasma cholesterol regulates soluble cell adhesion molecule expression in familial hypercholesterolemia. Circulation 1997;96:1381–5. [8] Utsumi K, Kawabe M, Hirama A, Ueda K, Kamada Y, Arii K, et al. Effects of selective LDL apheresis on plasma concentrations of ICAM-1, VCAM-1 and P-selectin in diabetic patients with arteriosclerosis obliterans and receiving maintenance hemodialysis. Clin Chim Acta 2007;377:198–200.
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Please cite this article in press as: Makino http://dx.doi.org/10.1016/j.transci.2017.08.014
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