Objective-Analysis of long-term (30 years) clinical history and response to treatment of 13 patients with the D374Y mutation of PCSK9 (PCSK9 patients) from 4 unrelated white British families compared with 36 white British patients with heterozygous familial hypercholesterolemia attributable to 3 specific mutations in the low-density lipoprotein (LDL) receptor gene (LDLR) known to cause severe phenotype. Methods and Results-The PCSK9 patients, when compared with the LDLR patients, were younger at presentation (20.8Ϯ14.7 versus 30.2Ϯ15.7 years; Pϭ0.003), had higher pretreatment serum cholesterol levels (13.6Ϯ2.9 versus 9.6Ϯ1.6 mmol/L; Pϭ0.004) that remained higher during treatment with simvastatin (10.1Ϯ3.0 versus 6.5Ϯ0.9 mmol/L; Pϭ0.006), atorvastatin (9.6Ϯ2.9 versus 6.4Ϯ1.0 mmol/L; Pϭ0.006), or current lipid-lowering therapy, including LDL apheresis and partial ileal bypass in 2 PCSK9 patients (7.0Ϯ1.6 versus 5.4Ϯ1.0 mmol/L; Pϭ0.001), and were affected Ͼ10 years earlier by premature coronary artery disease (35.2Ϯ4.8 versus 46.8Ϯ8.9 years; Pϭ0.002). LDL from PCSK9 patients competed significantly less well for binding to fibroblast LDL receptors than LDL from either controls or LDLR patients. Conclusions-These British PCSK9 patients with the D374Y mutation have an unpredictably severe clinical phenotype, which may be a unique feature for this cohort, and requires early and aggressive lipid-lowering management to prevent cardiovascular complications. Key Words: coronary disease Ⅲ atherosclerosis Ⅲ familial hypercholesterolemia Ⅲ statins Ⅲ ezetimibe F amilial hypercholesterolemia (FH) is a common autosomal dominant disorder caused by mutations in the lowdensity lipoprotein (LDL) receptor gene (LDLR) leading to defective catabolism of plasma LDL by the liver and characterized by elevated levels of LDL cholesterol, tendon xanthomas, and excessive deposition of cholesterol in the arterial wall, causing premature atherosclerosis. 1 An almost identical clinical syndrome to FH, called familial defective apolipoprotein B (apoB), can occur as a result of a dominantly inherited mutation of the ApoB gene, which encodes the ligand for the LDL receptor, causing impaired catabolism of LDL. 2 Recently, heterozygous missense variants in a gene named PCSK9 (protein convertase subtilisin/kexin9) have been described to cosegregate with hypercholesterolemia in families of European origin. [3][4][5][6] PCSK9 encodes a putative protease, which is a member of the subtilisin-like protein convertase family. 7,8 Its physiological role has not yet been elucidated, but there is substantial evidence that it is involved in cholesterol homeostasis. 9 -12 PCSK9 is responsive to sterols and is a putative sterol regulatory element-binding protein (SREBP) target in mice. 11,12 Adenovirus-mediated overexpression of wild-type PCSK9 in mice led to severe hypercholesterolemia by decreasing the amount of LDL receptor protein in the liver without reducing LDL receptor mRNA levels. 13 However, similar overexpression of 2 naturally occurring PCSK9 mis...

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Statin intolerance is a clinical syndrome whereby adverse effects (AEs) associated with statin therapy [most commonly statin-associated muscle symptoms (SAMS)] result in the discontinuation of therapy and consequently increase the risk of adverse cardiovascular outcomes. However, complete statin intolerance occurs in only a small minority of treated patients (estimated prevalence of only 3-5%). Many perceived AEs are misattributed (e.g. physical musculoskeletal injury and inflammatory myopathies), and subjective symptoms occur as a result of the fact that patients expect them to do so when taking medicines (the nocebo/drucebo effect)-what might be truth even for over 50% of all patients with muscle weakness/pain. Clear guidance is necessary to enable the optimal management of plasma in real-world clinical practice in patients who experience subjective AEs. In this Position Paper of the International Lipid Expert Panel (ILEP), we present a step-by-step patient-centred approach to the identification and management of SAMS with a particular focus on strategies to prevent and manage the nocebo/drucebo effect and to improve long-term compliance with lipid-lowering therapy.

Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are the drugs of choice in heterozygous familial hypercholesterolemia (FH), which has a high risk of ischemic heart disease. An open-label study was conducted to test the efficacy and safety of atorvastatin, a new synthetic HMG-CoA reductase inhibitor in proven FH. After a 4-week placebo phase, 22 subjects were randomized to either 80 mg atorvastatin at night (n = 11) or 40 mg twice a day for 6 weeks. The two dosage groups were well matched and had no difference in lipoprotein responses. After 6 weeks, the LDL cholesterol concentration was reduced by 57%, from 8.16 +/- 1.15 to 3.53 +/- 0.99 mmol/L (P < .001). The total cholesterol concentration decreased from 9.90 +/- 1.32 to 5.43 mmol/L (P < .001). HDL cholesterol concentration increased from 1.19 +/- 0.31 to 1.49 +/- 0.43 mmol/L (P < .001). Triglyceride concentrations decreased from 1.34 +/- 0.66 to 0.88 +/- 0.36 mmol/L (P < .01). Three subjects had single, transient increases of serum transaminase of up to twice the upper limit of normal. Apolipoprotein B concentration decreased significantly by 42%. Changes in apolipoproteins AI and (a) were not statistically significant. Nondenaturing gradient gel electrophoresis revealed increases in the size of smaller LDL particles in four subjects. Plasma fibrinogen concentration increased by 44%. The drug was well tolerated. One subject withdrew for personal reasons. Atorvastatin is a powerful and safe lipid-modifying agent for LDL cholesterol; it also modifies HDL cholesterol and triglyceride concentrations, and may suffice as a single agent for many subjects with heterozygous FH.