Cascade testing using DNA-mutation information is now recommended in the UK for patients with familial hypercholesterolaemia (FH). We compared the detection rate and mutation spectrum in FH patients with a clinical diagnosis of definite (DFH) and possible (PFH) FH. Six hundred and thirty-five probands from six UK centres were tested for 18 low-density lipoprotein receptor gene (LDLR) mutations, APOB p.Arg3527Gln and PCSK9 p.Asp374Tyr using a commercial amplification refractory mutation system (ARMS) kit. Samples with no mutation detected were screened in all exons by single strand conformation polymorphism analysis (SSCP)/denaturing high performance liquid chromatography electrophoresis (dHPLC)/direct-sequencing, followed by multiplex ligation-dependent probe amplification (MLPA) to detect deletions and duplications in LDLR.The detection rate was significantly higher in the 190 DFH patients compared to the 394 PFH patients (56.3% and 28.4%, p > 0.00001). Fifty-one patients had inadequate information to determine PFH/DFH status, and in this group the detection rate was similar to the PFH group (25.5%, p = 0.63 vs PFH). Overall, 232 patients had detected mutations (107 different; 6.9% not previously reported). The ARMS kit detected 100 (44%) and the MLPA kit 11 (4.7%). Twenty-eight (12%) of the patients had the APOB p.Arg3527Gln and four (1.7%) had the PCSK9 p.Asp374Tyr mutation. Of the 296 relatives tested from 100 families, a mutation was identified in 56.1%. In 31 patients of Indian/Asian origin 10 mutations (two previously unreported) were identified. The utility of the ARMS kit was confirmed, but sequencing is still required in a comprehensive diagnostic service for FH. Even in subjects with a low clinical suspicion of FH, and in those of Indian origin, mutation testing has an acceptable detection rate.

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There is a need to both better define the patient population eligible for LDL apheresis and to create unified European guidelines governing the use of apheresis. In addition to improving access to apheresis where appropriate, new therapies are needed to further decrease LDL-C and reduce the ongoing CVD risk in patients with severe hypercholesterolaemia.

This consensus statement addresses the current three main modalities of treatment of homozygous familial hypercholesterolaemia (HoFH): pharmacotherapy, lipoprotein (Lp) apheresis and liver transplantation. HoFH may cause very premature atheromatous arterial disease and death, despite treatment with Lp apheresis combined with statin, ezetimibe and bile acid sequestrants. Two new classes of drug, effective in lowering cholesterol in HoFH, are now licensed in the United Kingdom. Lomitapide is restricted to use in HoFH but, may cause fatty liver and is very expensive. PCSK9 inhibitors are quite effective in receptor defective HoFH, are safe and are less expensive. Lower treatment targets for lipid lowering in HoFH, in line with those for the general FH population, have been proposed to improve cardiovascular outcomes. HEART UK presents a strategy combining Lp apheresis with pharmacological treatment to achieve these targets in the United Kingdom (UK). Improved provision of Lp apheresis by use of existing infrastructure for extracorporeal treatments such as renal dialysis is promoted. The clinical management of adults and children with HoFH including advice on pregnancy and contraception are addressed. A premise of the HEART UK strategy is that the risk of early use of drug treatments beyond their licensed age restriction may be balanced against risks of liver transplantation or ineffective treatment in severely affected patients. This may be of interest beyond the UK.

Objectives: Refractory angina patients suffer debilitating chest pain despite optimal medical therapy and previous cardiovascular intervention. Cardiac rehabilitation is often not prescribed due to a lack of evidence regarding potential efficacy and patient suitability. A randomised controlled study was undertaken to explore the impact of cardiac rehabilitation on cardiovascular risk factors, physical ability, quality of life and psychological morbidity among refractory angina sufferers. Methods: Forty-two refractory angina patients (65.1 ± 7.3 years) were randomly assigned to an 8-week Phase III cardiac rehabilitation program or symptom diary control. Physical assessment, Progressive Shuttle Walk test, Hospital Anxiety and Depression Scale, Health Anxiety Questionnaire, the York Angina Beliefs scale, ENRICHD Social Support Instrument and SF-36 were completed before and after intervention and at 8-week follow-up. Results: Following cardiac rehabilitation, patients demonstrated improved physical ability compared with controls in Progressive Shuttle Walk level attainment (p = 0.005) and total distance covered (p = 0.015). Angina frequency and severity remained unchanged in both groups, with the control demonstrating worsening SF-36 pain scale (63.43 ± 22.28 vs. 55.46 ± 23.98, p = 0.025). Cardiac rehabilitation participants showed improved Health Anxiety Questionnaire reassurance (1.71 ± 1.72 vs. 1.14 ± 1.23, p = 0.026) and York Beliefs anginal threat perception (12.42 ± 4.58 vs. 14.35 ± 4.73, p = 0.05) after cardiac rehabilitation. Physical measures were broadly unaffected. Conclusions: Cardiac rehabilitation can be prescribed to improve physical ability without affecting angina frequency or severity among patients with refractory angina.