Non-HDL or LDL cholesterol in heterozygous familial hypercholesterolaemia: findings of the Simon Broome Register

PURPOSE OF REVIEW: The role of non-HDL-C in the identification and management of lipid disorders is not clearly defined, although UK guidelines recommend its wider use in assessing the need for lipid-lowering therapy and as a treatment target. RECENT FINDINGS: We examined the implications of the use of non-HDL-C as opposed to LDL-C in 253 people with hypercholesterolaemia before treatment and 573 after treatment in whom fasting total serum cholesterol, HDL-C and LDL-C had been recorded and the diagnosis of heterozygous familial hypercholesterolemia (heFH) was investigated by genetic testing. The difference and the limits of agreement between non-HDL-C and LDL-C calculated using the Friedewald formula were assessed in those with and without heFH-causing mutations. SUMMARY: There were 147 mutation-positive and 106 mutation-negative pretreatment participants and 395 mutation-positive and 178 mutation-negative patients receiving treatment. The difference between non-HDL-C and LDL-C pretreatment in mutation-positive people (mean LDL-C 7.73 mmol/l) was 0.67 mmol/l (95% CI 0.62-0.73) and posttreatment (mean LDL-C 4.71 mmol/l) was 0.62 mmol/l (95% CI 0.59-0.65) with wide limits of agreement of -0.02 to 1.37 and 0.07-1.18 mmol/l, respectively. Among patients with heterozygous familial hypercholesterolaemia, use of estimated LDL-C derived from non-HDL-C in place of calculated LDL-C may result in diagnostic misclassification and difficulty in assessing the true reduction in LDL-C with treatment, because of the wide inter-individual limits of agreement around the mean difference between non-HDL-C and LDL-C

Coronary heart disease mortality in treated familial hypercholesterolaemia: Update of the UK Simon Broome FH register

BACKGROUND AND AIMS: Patients with familial hypercholesterolaemia (FH) have an elevated risk of coronary heart disease (CHD). Here we compare changes in CHD mortality in patients with heterozygous (FH) pre 1992, before lipid-lowering therapy with statins was used routinely, and in the periods 1992–2008 and 2008–2016. METHODS: 1903 Definite (DFH) and 1650 Possible (PFH) patients (51% women) aged 20–79 years, recruited from 21 lipid clinics in the United Kingdom and followed prospectively between 1980 and 2016 for 67,060 person-years. The CHD standardised mortality ratio (SMR) compared to the population in England and Wales was calculated (with 95% Confidence intervals). RESULTS: There were 585 deaths, including 252 from CHD. Overall, the observed 2.4-fold excess coronary mortality for treated DFH post-1991 was significantly higher than the 1.78 excess for PFH (35% 95% CI 3%–76%). In patients with DFH and established coronary disease, there was a significant excess coronary mortality in all time periods, but in men it was reduced from a 4.83-fold excess (2.32–8.89) pre-1992 to 4.66 (3.46–6.14) in 1992–2008 and 2.51 (1.01–5.17) post-2008, while in women the corresponding values were 7.23 (2.65–15.73), 4.42 (2.70–6.82) and 6.34 (2.06–14.81). Primary prevention in men with DFH resulted in a progressive reduction in coronary mortality over the three time-periods, with no excess mortality evident post-2008 (0.89 (0.29–2.08)), although in women the excess persisted (post-2008 3.65 (1.75–6.72)). CONCLUSIONS: The results confirm the benefit of statin treatment in reducing CHD mortality, but suggest that FH patients with pre-existing CHD and women with FH may not be treated adequately

Coronary heart disease mortality in severe vs. non-severe familial hypercholesterolaemia in the Simon Broome Register

Background and aims: The International Atherosclerosis Society (IAS) has proposed that patients with “severe” FH (SFH) would warrant early and more aggressive cholesterol-lowering treatment such as with PCSK9 inhibitors. SFH is diagnosed if LDL-cholesterol (LDLC) > 10 mmol/L, or LDLC > 8.0 mmol/L plus one high-risk feature, or LDLC > 5 mmol/L plus two high-risk features. Here we compare CHD mortality in SFH and non-SFH (NSFH) patients in the UK prospective Simon Broome Register since 1991, when statin use became routine. Methods: 2929 definite or possible PFH patients (51% women) aged 20–79 years were recruited from 21 UK lipid clinics and followed prospectively between 1992 and 2016. The excess CHD standardised mortality ratio (SMR) compared to the England and Wales population was calculated (with 95% confidence intervals). Results: 1982 (67.7%) patients met the SFH definition. Compared to the non-SFH, significantly (p < 0.001) more SFH patients had diagnosed CHD at baseline (24.6% vs. 17.5%), were current smokers (21.9% vs 10.2%) and had a BMI > 30 kg/m2 (14.9% vs. 7.8%). The SMR for CHD mortality was significantly (p = 0.007) higher for SFH (220 (184–261) (34,134 person years, 129 deaths observed, vs. 59 expected) compared to NSFH of 144 (98–203) (15,432 person years, 32 observed vs. 22 expected). After adjustment for traditional risk factors, the Hazard Ratio for CHD mortality in SFH vs. NSFH was 1.22 (0.80–1.87) p = 0.36, indicating that the excess risk was largely accounted for by these factors. Conclusions: CHD mortality remains elevated in treated FH, especially for SFH, emphasising the importance of optimal lipid-lowering and management of other risk factors

Folic Acid Improves Endothelial Function in Coronary Artery Disease via Mechanisms Largely Independent of Homocysteine Lowering

Background— Homocysteine is a risk factor for coronary artery disease (CAD), although a causal relation remains to be proven. The importance of determining direct causality rests in the fact that plasma homocysteine can be safely and inexpensively reduced by 25% with folic acid. This reduction is maximally achieved by doses of 0.4 mg/d. High-dose folic acid (5 mg/d) improves endothelial function in CAD, although the mechanism is controversial. It has been proposed that improvement occurs through reduction in total (tHcy) or free (non–protein bound) homocysteine (fHcy). We investigated the effects of folic acid on endothelial function before a change in homocysteine in patients with CAD. Methods and Results— A randomized, placebo-controlled study of folic acid (5 mg/d) for 6 weeks was undertaken in 33 patients. Endothelial function, assessed by flow-mediated dilatation (FMD), was measured before, at 2 and 4 hours after the first dose of folic acid, and after 6 weeks of treatment. Plasma folate increased markedly by 1 hour (200 compared with 25.8 nmol/L; P<0.001). FMD improved at 2 hours (83 compared with 47 µm; P<0.001) and was largely complete by 4 hours (101 compared with 51 µm; P<0.001). tHcy did not significantly differ acutely (4-hour tHcy, 9.56 compared with 9.79 µmol/L; P=NS). fHcy did not differ at 3 hours but was slightly reduced at 4 hours (1.55 compared with 1.78 µmol/L; P=0.02). FMD improvement did not correlate with reductions in either fHcy or tHcy at any time. Conclusions— These data suggest that folic acid improves endothelial function in CAD acutely by a mechanism largely independent of homocysteine

Coronary heart disease mortality in severe vs. non-severe familial hypercholesterolaemia in the Simon Broome Register

Background and aims The International Atherosclerosis Society (IAS) has proposed that patients with “severe” FH (SFH) would warrant early and more aggressive cholesterol-lowering treatment such as with PCSK9 inhibitors. SFH is diagnosed if LDL-cholesterol (LDLC) > 10 mmol/L, or LDLC >8.0 mmol/L plus one high-risk feature, or LDLC >5 mmol/L plus two high-risk features. Here we compare CHD mortality in SFH and non-SFH (NSFH) patients in the UK prospective Simon Broome Register since 1991, when statin use became routine. Methods 2929 definite or possible PFH patients (51% women) aged 20–79 years were recruited from 21 UK lipid clinics and followed prospectively between 1992 and 2016. The excess CHD standardised mortality ratio (SMR) compared to the England and Wales population was calculated (with 95% confidence intervals). Results 1982 (67.7%) patients met the SFH definition. Compared to the non-SFH, significantly (p  30 kg/m2 (14.9% vs. 7.8%). The SMR for CHD mortality was significantly (p = 0.007) higher for SFH (220 (184–261) (34,134 person years, 129 deaths observed, vs. 59 expected) compared to NSFH of 144 (98–203) (15,432 person years, 32 observed vs. 22 expected). After adjustment for traditional risk factors, the Hazard Ratio for CHD mortality in SFH vs. NSFH was 1.22 (0.80–1.87) p = 0.36, indicating that the excess risk was largely accounted for by these factors. Conclusions CHD mortality remains elevated in treated FH, especially for SFH, emphasising the importance of optimal lipid-lowering and management of other risk factors

Folate Improves Endothelial Function in Coronary Artery Disease. An Effect Mediated by Reduction of Intracellular Superoxide?

Homocysteine is a risk factor for coronary artery disease (CAD). Folic acid lowers homocysteine and may improve endothelial function in CAD, although the mechanism is unclear. We investigated the effect of folic acid on endothelial function, homocysteine, and oxidative stress in patients with CAD. We also examined the acute effect of 5-methyltetrahydrofolate (5-MTHF), the principal circulating folate, on endothelial function in vivo and on intracellular superoxide in cultured endothelial cells. A randomized crossover study of folic acid (5 mg daily) for 6 weeks was undertaken in 52 patients with CAD. Ten further patients were given intra-arterial 5-MTHF. Endothelial function was assessed by flow-mediated dilatation (FMD). Folic acid increased plasma folate (P<0.001), lowered homocysteine by 19% (P<0.001), and improved FMD (P<0.001). FMD improvement did not correlate with homocysteine reduction. Malondialdehyde and total plasma antioxidant capacity, markers of oxidative stress, were unchanged. 5-MTHF acutely improved FMD (P<0.001) without altering homocysteine (P=0.47). In vitro, 5-MTHF abolished homocysteine-induced intracellular superoxide increase (P<0.001); this effect was also observed with folic acid and tetrahydrobiopterin. Our data support the beneficial effect of folic acid on endothelial function in CAD but suggest that the mechanism is independent of homocysteine. Reduction of intracellular endothelial superoxide may have contributed to the effect