Familial hypercholesterolemia and triglyceride metabolism

International Journal of Cardiology 147 (2011) 349–358

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International Journal of Cardiology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j c a r d

Review

Familial hypercholesterolemia and triglyceride metabolism Genovefa D. Kolovou ⁎, Peggy M. Kostakou, Katherine K. Anagnostopoulou 1st Cardiology Department, Onassis Cardiac Surgery Center, Athens, Greece

a r t i c l e

i n f o

Article history: Received 17 February 2010 Received in revised form 24 June 2010 Accepted 8 August 2010 Available online 9 September 2010 Keywords: Familial hypercholesterolemia Triglyceride metabolism Atherosclerosis Familial hypercholesterolemia treatment LDL apheresis

a b s t r a c t Familial hypercholesterolemia (FH) is a common autosomal disorder associated with hypercholesterolemia which usually results from a mutation in the coding region of the low density lipoprotein (LDL) receptor (R) activity. Only 20% of untreated heterozygote (h) FH men reach 70 years of age. Therefore, the diagnosis of hFH is a better predictor of coronary heart disease than risk-based algorithms. Fasting and postprandial hypertriglyceridemia are also considered as risk factors for atherosclerosis. The plasma triglycerides (TG)s are formed from two major sources; intestinally-derived chylomicrons and hepatically-derived very low density lipoproteins (VLDL). Potentially, atherogenic remnants of TG-rich lipoproteins accumulate in the postprandial state. In addition, TG-rich lipoproteins may promote the formation of atherogenic small dense LDL. In FH subjects, lipoprotein metabolism seems to be impaired and may contribute to premature atherosclerosis. This was documented in many studies in which mice lacking LDLR present hypercholesterolemia, increased plasma TG-rich lipoprotein remnants and develop premature spontaneous atherosclerosis. In this review, we focus on the current knowledge regarding TG metabolism on a selected clinically condition such as FH. Variation in clinical characteristics has been described between studies which may occur due to dissimilarity in the molecular defect of FH. Additionally, the relationship between TG levels in FH subjects and the development of atherosclerosis, as well as the appropriate treatment for these patients is analysed. © 2010 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Familial hypercholesterolemia (FH) is a common autosomal dominant disorder associated with hypercholesterolemia which usually results from mutations in the coding region of the low density lipoprotein (LDL) receptor (R) activity [1]. The phenotype of FH is characterized by elevated LDL cholesterol (N4.9 mmol/l or N188 mg/dl), a positive family history of dyslipidemia and early coronary heart disease (CHD) as well as the presence of tendon xanthomas and premature atherosclerosis [2–4]. Causal mutations in other genes have been incriminated for hypercholesterolemia. The R3500Q mutation in the apolipoprotein (apo) B gene (familial defective apo B) results in a phenotype that is slightly milder than that caused by mutations in LDLR [5]. Mutations in a third locus, PCSK9, have been identified to result in hypercholesterolemia [6]. Analysis of family pedigrees has revealed the presence of an autosomal recessive hypercholesterolemia (ARH), where the disease-causing gene encodes an adaptor protein that binds to the LDLR clathrin-coat network [7]. The heterozygote (h) frequency is estimated to be 1/200–500 in most populations [3,4,8,9]. Clinically documented CHD usually occurs at a mean age of 45–48 years in men

⁎ Corresponding author. Onassis Cardiac Surgery Center, 356 Sygrou Ave 176 74 Athens, Greece. Tel.: + 30 210 9493520; fax: + 30 210 9493336. E-mail address: [email protected] (G.D. Kolovou). 0167-5273/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2010.08.009

and 55–58 years in women [4] while only 20% of untreated hFH men reach 70 years of age [4]. The plasma levels of LDL cholesterol in FH homozygotes are very high, irrespectively of diet or lifestyle variations. [10]. Nevertheless, the onset and severity of CHD varies among FH patients even with identical mutations [11,12]. This is even more pronounced in heterezygotes for FH where the level of LDL cholesterol can be additionally influenced by life style factors such as physical exercise, control of food calorie intake, psychological awareness of the disease and compliance regarding medications. Epidemiological data support that elevated fasting plasma triglyceride (TG) concentrations also contribute to atherosclerosis and are an independent risk factor for CHD. Furthermore, the postprandial hypertriglyceridemia is considered as a risk factor for atherosclerosis, too [13–19]. Potentially atherogenic remnants of TG-rich lipoproteins, namely chylomicrons (CM), very low-density lipoproteins (VLDL), accumulate in the postprandial state [16,20,21]. The high levels of TGrich lipoproteins may promote the formation of atherogenic small dense LDL [22,23]. Thus, one of the explanations of heterogeneity in the manifestation of atherogenic disease in FH patients could lie in the TG metabolism. Recent evidence raises the possibility that TG involvement has been significantly underestimated. Here, we review the current knowledge regarding TG metabolism focusing on a selected clinically condition such as FH. This review also demonstrates the influence of TG on CHD manifestation in patients with FH.

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2. TG metabolism in the fasting state Plasma TGs are formed by two major sources; intestinally-derived CM and hepatically-derived VLDL [24,25] (Fig. 1). CMs are characterized in our minds as solely TG-rich lipoproteins, although each particle contains 40 times more cholesterol than LDL [26] and CMs transport three times more cholesterol than LDL particles over a period of 24 h [27]. In the circulation, the TGs are hydrolysed by lipoprotein lipase (LPL) and they form CM remnants. The removal of CM remnants is carried out by muscle and adipose tissue [28] where endocytosis takes place. The endocytosis of CM remnants could be via the LDLR and LDLR related protein (LRP) as well as via other receptors. The second source of TG derives from VLDL. The formation of VLDLs in the liver depends firstly on the availability of hepatic cholesterol substrate, that controls the expression of LDLRs and partly regulates the production of VLDL, and secondly on fatty acid supplies to the liver and hepatic TG pools [29]. High availability of cholesterol substrate reduces hepatic cholesterol synthesis and the secretion of VLDL decreases followed by the upregulation of LDLRs [29,30] (Table 1). This may enhance the removal of CM and VLDL remnants. The removal of VLDL follows the same pathway as the CM remnants [31]. The LDLR acts as both apo B-100- and apo E receptor. However, LDLRs have a higher affinity for apo E-containing particles compared with the binding to LDL, which has only apo B-100 as a structural apolipoprotein [32]. It was shown that lipoproteins containing apo E have better affinity for LDLRs than those containing only apo B [33]. The relative contribution of the LDLR for the clearance of CM remnants is still unclear and controversial [34–42]. 2.1. TG metabolism postprandially The rate of TG clearance is the result of many variables [14,43] such as the size of capillary beds, the amount of active LPL and the competition between VLDLs and CMs. Xiang et al. have shown that the removal of TG from CMs is 10 times greater than that from VLDL after a mixed meal [44]. Furthermore, the number of VLDL particles is much higher than that of CMs in the postprandial state (about 20:1) and the increase in VLDL particle number in the postprandial state is greater than the increase in CM particle number [24,45]. In the early postprandial period (the first 3 h after a meal) smaller sized CMs are secreted. Later in the postprandial period, de novo-formed larger

CMs are secreted [46,47]. The smaller sized CMs are considered to be atherogenic [46,48]. In healthy subjects, VLDLs secreted by the liver are not considered to be atherogenic. In the hyperTG state (transient accumulation of CMs, VLDLs and their remnants), the rate of cholesteryl ester transfer from high density lipoprotein (HDL) to VLDL is elevated resulting in the secretion of large VLDL particles and the formation of small dense LDL particles [49,50]. It has been proposed that elevated plasma TG concentration promotes the cholesteryl ester exchange reactions mediated by cholesteryl ester transfer protein (CETP, glycoprotein secreted mainly from the liver) [51,52]. When the level of VLDLs is within the normal range, the CETP-mediated transfer of HDL cholesteryl esters is directed preferentially to LDL particles [53]. When the concentration of VLDL particles is increased, the cholesteryl esters of HDL are preferentially transferred by CETP to larger VLDL particles [53] (Table 1). Overall, during alimentary lipemia, the CETPmediated transfer of neutral lipids (cholesteryl esters and TGs) between plasma lipoprotein particles is increased [54–56], allowing transformation of cholesteryl ester-enriched HDL into TG-rich HDL particles which become a substrate for hepatic lipase [57,58] and are cleared more rapidly from the circulation [59], leading to low serum HDL cholesterol levels [60]. 3. FH and TG metabolism in the fasting state In FH subjects, TGs are not usually elevated, suggesting that production and clearance of CMs are normal. In 1980, Angelin [61] studied the plasma endogenous TG kinetics in five unaffected and eight affected (heterozygous) siblings with FH and concluded that abnormal plasma TG metabolism was not a feature of heterozygous FH. Since then many studies, including ours, have been evaluated the TG metabolism in FH subjects (as will be discussed in the later part) (Fig. 2). Radiolabeling studies indicated that patients with FH are characterized by a decreased clearance of LDL particles [62], which is in agreement with the underlying LDLR defect. In the absence of LDLR, the upregulation of VLDLR in the liver is observed [63]. Cummings at al. [62] reported an increased secretion of VLDL apo B. Also, Tremblay et al. [64] reported 50% and 109% increases in VLDL apo B production in heterozygous and homozygous FH, respectively. Furthermore, Horton et al. [65] have demonstrated that knockout mice showed an increased apo B secretion in the absence of the LDLR. Similarly, Liao et al. [66] found that hepatocytes from LDLR knockout mice secreted

Dietary TG, C Synthesized TG Liver

LDLR, LDLR-LRP, LRPα2M, and others CM Intestine

CMR Muscle and adipose LPL

tissue vessels

C = cholesterol, CM = chylomicrons, CMR = chylomicron remnants receptors, LDLR = low density lipoprotein receptor, LDLR-LRP = LDLR-related protein, LPL = lipoprotein lipase, LRP-α2M = LRP-α2-macroglobulin, TG = triglycerides. Fig. 1. TG metabolism.

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Table 1

TG metabolism in the fasting state TG metabolism postprandially

FH and TG metabolism in the fasting state FH and postprandial hypertriglyceridemia

Clinical studies

Subjects

Results

Chan et al. [30] Lechleitner et al. [36] Schneeman et al. [25] Guerin et al. [57]

35 ♂ with MS Macrophages of 17 healthy sb 7 healthy ♂ 12 IIB hyperlipidemic pts, 14 controls 602 sb 12 healthy ♂ 836♂, 549♀ 5 controls, 7 FH sb 80 FH ♂ and♀, 11 controls

C ratio was inversely associated with TRL, RLP-C and apoB-48 levels Postprandial LDL leads to ↑CE accumulation VLDL N CM accumulation after meal HDL-CE → VLDL-1 postprandially leads to ↑ atherogenic CE-rich remnant particles

Sharrett et al. [14] Karpe et al. [46] Kolovou et al. [79] Tremblay et al. [64] Anagnostopoulou et al. [101] Kolovou et al. [103] Wiegman et al. [124]

TG in FH and atherosclerosis Postprandial lipemia in FH Dane-Stewart et al. and atherosclerosis [106] LDLR knockout mice Barcat et al. [134] Diet Jakulj et al. [151] Exercise Katzmarzyk et al. [156] Drugs Tsouli et al. [161] LDL apheresis Coker et al. [176] Gene therapy Shichiri et al. [187] Liver transplantation

Kakaei et al. [196]

14 FH ♂, 12 controls 1034 children from FH kindreds

Predictors of postprandial responses were smoking, diet, creatinine, and alcohol Largest CM/CM remnant species are marginated to the vascular wall after meal ♀ had ↑TC, ↑ HDL-C,↓TGs,↓ TC/HDL-C ratio than ♂ 50% and 109% ↑ VLDL apoB production in hFH and hom FH respectively Gender and TaqIB polymorphism of CETP were associated with TG variance after oral fat tolerance test hFH had↑ TG response to fatty meal compared to controls ↑LDL-C, ↑Lp(a), ↑TGs, ↓ HDL-C levels identify FH kindreds with ↑CVD risk

15 FH sb, 15 controls

hFH pts have ↑TG-rich lipoprotein remnants causally related to atherosclerosis

HLR−/−,LDLR−/− mice 42 FH children 342 ♂, 268 ♀ adolescents 80 hFH, 80 controls 10 hom FH children Watanabe Heritable Hyperlipidemic Rabbits 2 hFH adolescents

↑ TG-rich lipoproteins and their remnants and premature atherosclerosis Plant stanols↓LDL-C levels Physical activity is strongly associated with CHD risk factors Statin treatment ↓ achilles tendon thickness LDL apheresis combined with drugs leads to safe and effective ↓ LDL-C Transferrin-facilitated intravenous transfer of cationic liposome LDLR gene complexes Lipid concentrations returned to normal range after the operation, remaining over 6 months of follow-up.

apoB: apolipoprotein B, CE: cholesteryl ester, CETP: cholesterol ester transfer protein, CHD: coronary heart disease, CVD: cardiovascular disease, CM: chylomicron, FH: familial hypercholesterolemia, HDL: high density lipoprotein, hFH: heterozygotes for FH, HLR: hepatic lipase receptor, hom FH: homozygotes for FH, LDL: low density lipoprotein, LDLR: LDL receptor, Lp(a): lipoprotein (a), MS: metabolic syndrome, pts: patients, RLP-C: remnant-like particle-cholesterol, sb: subjects, TC: total cholesterol, TG: triglyceride, TRL = triacylglycerol, VLDL: very low density lipoprotein.

more apoB-100 than did hepatocytes from wild-type. Also, Twisk et al. [67] suggested that the LDLR could affect the production rate of apo B by promoting the uptake of newly secreted apo B-containing lipoproteins at the cell surface. This means, that null mutations would result in higher VLDL apo B secretion than defective mutations, because defective LDLRs could still associate with nascent apo B-100 and make possible its removal from the endoplasmic reticulum or its degradation [68]. However, in the study with transgenic mice, Millar et al. [69] have noticed that the LDLR did not have any effect on the production rate of VLDL apo B. Although, few years later Millar et al. [70] showed that receptor-defective FH patients had a total apo B

production similar to controls, whereas receptor-negative FH patients had a significantly greater total apo B production than controls. Soutar, Myant, and Thompson [71,72], with a radiolabeling technique, showed that the VLDL apo B production rate of FH homozygotes was not different from that of heterozygotes and control subjects, demonstrating that the LDLR had no effect on apo B production. Also, Uauy et al. carried out a kinetic study of three receptor-negative FH homozygotes [73] and found that hepatic production of apo Bcontaining lipoproteins was not significantly increased in these patients. Trembley et al. [64] reported that the elevated apo Bcontaining lipoproteins found in FH subjects are related to both

1. ↑↑ Synthesized TG

Liver

LDLR 2. LDL compete with 4. Impaired clearance

CMRs

of ppl particles

LDL CMR

5. Accumulation of small, dense CMs even in the fasting state 3. CMR require 4 Rs, while LDL particle 1 R

CM = chylomicrons, CMR = chylomicron remnants receptors, LDL = low density lipoprotein, LDLR = LDL receptor, ppl = postprandial lipemia, Rs = receptors, TG = triglycerides. Fig. 2. FH and TG metabolism.

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overproduction of VLDL apo B-100 and reduction in the LDL apo B-100 fraction catabolism rate. Moreover, Fisher et al. [74,75] reported a lower VLDL apo B production rate but an increased direct production of intermediate density lipoprotein (IDL) and LDL by severely altered conversion rate of VLDL to LDL (nearly twice compare to healthy). On the other hand, James et al. [76] reported that VLDL apo B production rate of FH homozygotes was increased by 54% as compared with that of controls, while Zulewski et al. [77] found a 33% increase in FH heterozygotes. The increased VLDL apo B production rates in subjects with FH can lead to increase in fasting serum TG concentrations. These variations found between studies may occur due to dissimilarity in molecular defect of FH as was already mentioned above and factors which influence the VLDL production and catabolism (variations in ethnicity, age, gender, apo E polymorphism, insulin resistance, and body mass index [78–80]) (Table 1). Overall, in FH, the fraction catabolism rate of LDL and to a lesser extent of VLDL- and IDL is decreased. Also, the production rate seems to be altered, with the majority of studies showing increased VLDL, IDL, and LDL production Febbraio et al. suggested close relationships between fatty acid translocase receptor (FAT/CD36, which is a member of scavenger receptor SR-B receptor [81]) and LPL gene [81], and similarly between VLDLR and LPL [82]. Degrace et al. demonstrated a concomitant induction of the expression of VLDLR, LPL and FAT/CD36 in liver, which suggests a functional cooperation of these proteins to face the lipoprotein (oxidize LDL) abundance [63]. The stimulation of FAT/CD36 and LPL can result in the greater delivery of fatty acids to liver cells especially with the liver TG infiltration. It appears that mRNA levels of hepatic lipase may offer another clearance pathway for apoB-100-containing lipoproteins independent of LDLR [83]. Furthermore, Jones et al. [84] found that the clearance of circulating VLDL remnants is largely preserved in mice lacking autosomal recessive hypercholesterolemia, which indicates that the requirements for hepatic LDLR function are ligand specific. The preservation of VLDL remnant clearance likely contributes to the reduced clinical severity observed in individuals with autosomal recessive hypercholesterolemia compared with patients with no LDLR function [9,85–93]. This finding is in agreement, that VLDL metabolism is very important in FH subjects, since the impaired catabolism may attenuate the early manifestation of the CHD in FH patients. Additionally, despite marked increases in VLDL secretion, overexpression of sterol regulatory element binding protein-1a (SREBP-1a) does not increase circulating lipoprotein levels except when the LDLR is inactivated. Mice that overexpress SREBP-1a and lack functional LDLR are severe hyperlipidemic [65]. Moreover, on top of what was already discussed the FH subjects may show increased plasma TG-rich lipoproteins in a variable spectrum that depends on the other genetic loci. Takada et al. [94] found that the gene–gene interaction influences the clinical phenotype of FH. They demonstrated that apo H Leu/Leu alleles, which carried the LDL mutation exhibit greater elevation of plasma TG levels compared to other members of the apo H genotypic group (apo H takes place in removing TGs from plasma and enhances LPL).

4. FH and postprandial hypertriglyceridemia The pathophysiology of postprandial hypertriglyceridaemia is not completely clear. It has been reported that a number of gene loci, such as those of apo E, LPL, apo CIII, apo A1, apo A4, CETP and of fatty acidbinding protein (FABP) are related to the fat load response [95–98]. Therefore, postprandial lipemia may be a polygenic phenomenon. Ottestad et al. showed that in FH patients with hypertriglyceridemia, the HDL particles are TG-enriched [99]. Thus, the HDL-TG enriched particles are cleared more rapidly from the circulation [59], resulting in lower serum HDL levels.

The measurement of TG levels postprandially reflects, to some degree, the behavior of CMs [100]. The postprandial lipemia in FH patients was evaluated only by few investigators, including us [101– 108] (Table 1). It was found that patients with FH have delayed clearance of CMs. Since CMs are partially catabolised by hepatic LDLR [108], the reduced activity of these receptors in FH patients may lead to increased accumulation of CM remnants [100,107]. Castro-Cabezas et al. found a two-fold delay in the clearance of retinol from plasma in a density range corresponding to remnant particles [107]. However, in the same study, the clearance of TGs and palmitate in the CM fraction were not different. They proposed an explanation for that; LDL particles compete for the same removal pathway as CMs and their remnants, in a manner similar to the competition between CMs and VLDL [107]. Further evidence [108] showed that the clearance of postprandial lipoproteins is significantly impaired in subjects with FH and that there is a substantial accumulation of small, dense CM particles even in the fasting state. Additionally, CM remnants were found to require four receptors for binding compared with one receptor per LDL particle. This suggests that in LDLR-deficient states, CM remnant clearance may be compromised [109]. On the other hand, Watts et al. [110] reported that the catabolism of CM remnants from plasma is not impaired in FH and that the hepatic uptake of these particles is not dependent on functional LDLR. If this is a case, the abnormal remnant accumulation should not have occurred in FH patients which is opposite to what was found by others [107,108] and our group [104]. Moreover, in hFH subjects the production rate of the VLDL is increased and this is even more pronounced in FH homozygotes [104]. The VLDL production rate has been reported 50% higher in heterozygotes and 109% in homozygotes when compared with healthy controls [104]. Based on animal studies, Twisk et al. [67] showed that the LDLR binds apo B intracellularly and targets it for degradation, as well as captures newly secreted VLDL for internalization and turnover. Therefore, in cohorts that have LDLR insufficiency, neither presecreted apo B degradation nor re-uptake of nascent VLDL is carried out to the same degree as in subjects with physiological LDLR, thus resulting in an increased VLDL production rate. This process creates VLDL particles enriched in cholesterol and depleted in TGs and could explain the low TG levels observed in most of FH patients by others [111,112] and us [113]. Summarizing, in FH subjects the metabolism of postprandial lipoproteins appears to be impaired and may contribute to premature atherosclerosis (as will be discussed in the later part). 5. TG in FH and atherosclerosis Although TGs are not found in atheromatous plaques [19,114], they are involved in atherogenesis by few mechanisms such as: 1) they are carriers of cholesteryl esters to the vessel wall [19,115], 2) they induce endothelial dysfunction [116–119], and 3) hypertriglyceridaemia is accompanied by small dense LDL (which is more susceptible to oxidation) [15,120–122], low concentrations of HDL [15,123] and small dense HDL [59]. Raised TG levels may also be associated with a higher risk of premature CHD in patients with hFH [124,125] (Table 1). The role of increased TG levels as a risk factor for CHD has also been described in a rare condition (Tangier Disease) [13]. 5.1. Postprandial lipemia in FH and atherosclerosis Patients with FH and disturbances in postprandial lipoprotein metabolism have higher risks for coronary artery disease [125]. Animal studies have shown that a deficiency in the LDLR is associated with a delayed chylomicron remnant removal since, among other receptors, the LDLR is used for remnant hepatic uptake [40,41,126]. Our studies [104,127] and other's studies [107,108,125] have demonstrated a significant postprandial increase in TG-rich lipoproteins in hFH patients

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compared to normolipidemic controls. Dane-Stewart et al. demonstrated that patients with hFH present elevated plasma concentrations of TGrich lipoproteins remnants, including those of intestinal origin, which is causally related to atherosclerosis [106].

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beef significantly reduced LDL-cholesterol concentrations between 8% and 15% at a dose of 1.5–3 g/day [152]. Furthermore, substitution of soya protein for animal protein can reduce total cholesterol, LDLcholesterol and apo B levels in children and adolescents, preventing of early vascular disease [153].

6. LDLR knockout mice 7.2. Exercise The consequences of LDL deficiency in mice are difficult to predict because mice like rats, have a basal difference in metabolism compared to species that have been studied [128]. In mice and rats, a substantial fraction of the VLDL secreted from liver contains apo B-48 instead of apoB-100 [129–131]. Remnants derived from apoB-48 are cleared into the liver and are not converted to LDL [132]. Some of this clearance may be mediated by the chylomicron remnant receptor. For this reason, LDLR deficiency in mice may not predict rise of plasma LDL level as profoundly as it does in Watanabe-heritable hyperlipidemic (WHHL) rabbits [133]. However, many studies report that mice lacking LDLR present hypercholesterolemia, increased plasma TG-rich lipoproteins remnants and show premature spontaneous atherosclerosis [134–136] (Table 1). Plasma TG levels are referred as normal [137]. Additionally, Knouff et al. reported severe atherosclerosis in mice expressing human apo E but lacking the LDLR, even when fed normal chow diet [138]. The hypercholesterolemia of LDLR−/− mice is due to the slow clearance rates of VLDL, IDL, and LDL, indicating that LDLR is responsible in part for the low levels of VLDL, IDL, and LDL in wild-type mice [137,139]. Moreover, in LDLR knockout mice fed a diet containing ezetimibe (0–10 mg/day/kg body weight), cholesterol absorption was reduced up to 91% and plasma total cholesterol concentrations decreased by up to 18%. It seems that blocking cholesterol absorption prevented the accumulation of VLDLs and LDLs in the circulation of LDLR−/− mice fed a lipid-rich diet. [140]. Also, fenofibrate improves lipid metabolism in LDLR knockout mice [141]. 7. FH and treatment Once identified, FH homozygotes should begin drug therapy as soon as possible. Early detection and treatment of FH is critical to prolong the life of these patients. FH heterozygotes can be placed on a diet and drug management program. Severe and resistant cases are treated with LDL apheresis in combination with drug therapy. Also, gene therapy may help these patients in the future. 7.1. Diet In FH, the usually recommended diet and lifestyle modifications do not achieve the target LDL-cholesterol concentrations advised by US National Cholesterol Education Program [142]. However, many of the drugs found to be effective in treating adults with this disease are not licensed for use in children; therefore, diet is the main treatment for children with FH. Τhe recommended diet includes lower cholesterol intake but also, lower intake of saturated fatty acids since saturated fatty acids seem to suppress LDLR activity [143–145]. This diet limits saturated fat intake to b7% of total caloric intake and cholesterol intake to b200 mg/d. [146]. Thus, diet can lead to a reduction of total plasma cholesterol but the combination with bile acid-binding resin therapy has even better results in heterozygous FH children [147]. In addition to the cholesterol-lowering diet, several other dietary interventions have been suggested as some nutritional supplements (pectin, polyphenols, and phytosterols). Phytosterols seem to represent the most effective supplementation [148–150]. Jukulj et al. demonstrated that a daily intake of 2.0 g of stanols significantly decreased the levels of total cholesterol by 7.5% and LDL cholesterol by 9.2% in FH patients. [151]. Also, in a review of 19 randomized controlled trials, it was concluded that phytosterols/stanols incorporated in different food vehicles such as margarine/fat spreads, butter, salad dressings, mayonnaise, chocolate, low fat yogurt, bakery products and ground

Most recent data indicate physical activity as an independent protective factor in the development of cardiovascular disease, due to the impact of exercise on the lipoprotein profile. Tolfrey et al. in their review [154], demonstrated that cross-sectional studies support the role of exercise in the modification of lipoprotein profiles in children too, indicating improvements in HDL cholesterol levels, the ratio of total to HDL cholesterol, and in the ratio of LDL cholesterol to HDL cholesterol, with little effect on total cholesterol levels. The impact of physical activity on the lipoprotein profile varies from 5% to 30% in several studies [154–158]. On the other hand, some studies show no relationship between lipid concentrations and aerobic fitness, while others indicate changes that are gender specific or are following physical activity variations [154,155,157,159]. Different methods of assessing aerobic capacity and maximal oxygen consumption (Vo2) may be responsible for these differences. 7.3. Drugs Statins (inhibitors of ß-hydroxy-ß-methylglutaryl coenzyme A reductase) are the drugs of first choice in patients with FH. The regulatory response to these drugs is to increase LDLR expression, which in turn leads to decreased plasma LDL levels. Marais et al. demonstrated a 57% reduce in LDL concentration after 6 weeks of atorvastatin treatment in heterozygous FH patients [160] and also, atorvastatin treatment reduced achilles tendon thickness [161] (Table 1). Furthermore, rosuvastatin decreased LDL cholesterol by 58%, increased HDL cholesterol by 12%, [8] and reduced carotid artery intima-media thickness in FH subjects [162]. Also, treatment with simvastatin decreased LDL concentration by 36% as it normalized the removal of cholesterol esters [163]. Finally, Shafiq et al. reported that statins may have good efficacy for the treatment of FH in children [164]. However, the lipid-lowering effect of statin treatment in FH patients presents significant variation, most likely depending on the type of LDLR mutation [165–172]. Therefore, many patients require combination therapy to achieve the desired cholesterol concentrations like colestimide/cholestyramine (the conventional resin) or ezetimibe when statin administration is insufficient [173,174]. Also, bile acid sequestrants, niacin and fibrates may be used supplementally [3,146]. 7.4. LDL apheresis LDL apheresis combined with lipid-lowering drugs, leads to a safe and effective decrease of the mean LDL-cholesterol levels [175] even in pediatric homozygous FH and pregnancy [176,177]. In Onassis Cardiac Surgery Center, we treat 16 FH patients with LDL apheresis, reporting significant decrease of total cholesterol, LDL and TG plasma levels [178]. For FH treatment, the drugs which can be used in combination with LDL apheresis are statins with or without ezetimibe, leading to greater prevention of atherosclerosis [177,179,180]. Coker et al. reported chronic reduction in LDL cholesterol ranged from 18 to 52%, with a mean level of 36.4 ± 11.7% in FH patients aged 8.4 ± 4.7 years old, following LDL apheresis therapy [176]. There are several methods for the implementation of LDL apheresis, being used weekly or biweekly in order to reduce LDL cholesterol and lipoprotein (a) [Lp(a)] without excessive decrease of HDL cholesterol [181]. According to Thompson and HEART-UK LDL Apheresis Working Group, LDL apheresis is the treatment of choice for: 1) FH homozygous children

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aged N7 years old if their serum cholesterol level cannot be reduced by N50% and/or decreased to ≤9 mmol/l (346 mg/dl) by drug therapy, 2) patients with heterozygous FH or a bad family history of premature cardiac death whose coronary heart disease progresses and LDL cholesterol remains N5.0 mmol/l (192 mg/dl) despite maximum drug treatment, 3) patients with aggressive coronary heart disease and Lp(a) N60 mg/l whose LDL cholesterol remains N3.2 mmol/l (123 mg/dl) despite maximum drug treatment [182]. 7.5. Experimental treatment Only a small proportion of patients with FH reach the LDLcholesterol treatment target, so there is a need for new treatment options in FH subjects in order to further decrease the LDL-cholesterol levels. 7.5.1. Gene therapy Gene therapy for FH could be used to decrease the morbidity and mortality in these patients. Among the current recombinant viral vectors, only adenoviral vectors produce the levels of gene expression required for a therapeutic response. For example, adenoviral vector transfer of the LDLR gene temporarily normalized cholesterol levels in mouse [137] and rabbit models of FH [183,184], while retroviral vector transfer was unsuccessful at normalizing cholesterol levels in rabbits [185] and humans [186]. Shichiri et al. demonstrated that transferrin-facilitated intravenous delivery of cationic liposome LDLR gene complexes could be an important additional therapy for the treatment of FH, since intravenous treatment dose decreased plasma total and LDL cholesterol concentrations in combination with an increased level of LDLR mRNA transcripts in leukocytes. [187]. Moreover, Tomita et al. identified that the administration of the human LDLR plasmid by the HVJ-liposome method into the liver resulted in a decrease of total cholesterol level in FH subjects, suggesting a possible novel gene therapy for FH [188]. The adenovirus-mediated transfer of VLDLR gene into the LDLR knockout mice liver seems to enhance the ability to clear the IDL particles, leading to a significant decrease of plasma IDL/LDL particles [189,190]. Furthermore, helper-dependent adenovirus-mediated delivery of VLDLR into hypatokytes resulted in a long-term reduction of plasma cholesterol and inhibited atherosclerosis evolution in LDLR knockout mice [191]. LDLR could be recognized as a foreign protein in FH subjects, so gene therapy including VLDLR instead of LDLR for FH patients may be rational [192]. 7.5.2. Liver transplantation Several studies support that liver transplantation offers a highly effective treatment for FH [193–195]. Kakaei et al. reported cases of liver transplantation with satisfactory results [196]. Plasma lipid levels return to normal range, remain at this range [196,197] and also, no signs of cardiovascular or atherosclerotic lesions are noted for a long term after liver transplantation [197]. It is important that all FH patients must incur the necessary cardiac exams before the operation [196]. 8. Conclusions FH is associated with CHD due to the elevated LDL concentrations but also, TG levels and postprandial hypertriglyceridemia represent an independent risk factor for CHD. FH subjects are characterized by a decreased clearance of LDL particles and increased production of VLDL apo B, suggesting that the LDLR could affect the production rate of apo B by promoting the uptake of newly secreted apo B-containing lipoproteins at the cell surface. However, there are other studies demonstrating that the LDLR had no effect on apo B production. These differences found between studies may occur due to dissimilarity in molecular defect of FH.

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