Ian McDowell

Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study.

Aims To examine the changes in coronary, all-cause, and cancer mortality in patients with heterozygous familial hypercholesterolaemia (FH) before and after lipid-lowering therapy with statins. Methods and results A total of 3382 patients (1650 men) aged <80 years were recruited from 21 lipid clinics in the United Kingdom and followed prospectively between 1980 and 2006 for 46 580 person-years. There were 370 deaths, including 190 from coronary heart disease (CHD) and 90 from cancer. The standardized mortality ratio (compared with the population in England and Wales) was calculated before and from 1 January 1992. In patients aged 20–79 years, CHD mortality fell significantly by 37% (95% CI = 7–56) from 3.4- to 2.1-fold excess. Primary prevention resulted in a 48% reduction in CHD mortality from 2.0-fold excess to none, with a smaller reduction of nearly 25% in patients with established disease. Coronary mortality was reduced more in women than in men. In patients without known CHD at registration, all-cause mortality from 1992 was 33% (21–43), lower than in the general population, mainly due to a 37% (21–50) lower risk of fatal cancer. Conclusion The results emphasize the importance of early identification of FH and treatment with statins.

Integrating provision of specialist lipid services with cascade testing for familial hypercholesterolaemia.

Purpose of review To highlight the unmet need for identifying individuals with familial hypercholesterolaemia and exploring the implications that this will have for local and national healthcare services. Recent findings A pathway utilising DNA testing for the diagnosis of familial hypercholesterolaemia, and subsequent cascade testing has been developed in Wales. Summary Undiagnosed familial hypercholesterolaemia carries a high risk of cardiovascular disease, which is easily preventable with pharmacotherapy, if individuals are appropriately diagnosed, and affected family members identified. The use of DNA testing is cost-effective and allows for efficient cascade testing. This has implications for local services and highlights unmet educational and clinical requirements in clinical lipidology.

A comparison of the effect of advice to eat either ‘5-a-day’ fruit and vegetables or folic acid-fortified foods on plasma folate and homocysteine

Objective: To assess and compare the effects of natural folate (100 µg) with those of folic acid from fortified sources (100 µg/day) on plasma folate and homocysteine.Design: Randomized controlled trial (parallel groups).Setting: Men and women living in South Wales, UK.Subjects: A total of 135 healthy individuals recruited from the local workforce and blood donor sessions. All subjects possessed the ‘wild-type’ CC genotype for C677T polymorphism in methylenetetrahydrofolate reductase (MTHFR).Interventions: Subjects underwent one of the following dietary interventions for 4 months: (1) fortified diet—usual diet plus 100 µg/day folic acid from fortified foods; (2) natural folate diet—usual diet plus 100 µg/day folate from natural sources; (3) control—usual diet.Results: The fortified group increased reported intake of folic acid from fortified foods compared to other groups (P<0.001) achieving an extra 98 µg/day (95% CI 88–108). The natural folate group increased reported intake of natural source folates compared with the other two groups (P<0.001), but achieved a mean increase of only 50 µg/day (95% CI 34–66). Plasma folate increased (P<0.01) by a similar amount in both intervention groups compared to controls (fortified group 2.97, 95% CI 0.8–5.1; natural group 2.76, 95% CI 0.6–4.9. Plasma homocysteine, vitamins B6 and B12 were not significantly changed.Conclusions: Subjects achieved increases in folate intake using fortified foods more easily than by folate-rich foods, however both sources increased plasma folate by a similar amount. These levels of intake were insufficient to reduce homocysteine concentrations in MTHFR CC homozygotes, but may be more effective in other genotypes.Sponsorship: This study was supported by the UK Ministry of Agriculture, Fisheries and Foods (latterly UK, Food Standards Agency, Project Reference N05002). The Kellogg Company of Great Britain provided funding for reimbursement of subjects for the cost of fortified foods.

Clinical experience of scoring criteria for Familial Hypercholesterolaemia (FH) genetic testing in Wales

BACKGROUND/OBJECTIVE Familial Hypercholesterolaemia (FH) is caused by mutations in genes of the Low Density Lipoprotein (LDL) receptor pathway. A definitive diagnosis of FH can be made by the demonstration of a pathogenic mutation. The Wales FH service has developed scoring criteria to guide selection of patients for DNA testing, for those referred to clinics with hypercholesterolaemia. The criteria are based on a modification of the Dutch Lipid Clinic scoring criteria and utilise a combination of lipid values, physical signs, personal and family history of premature cardiovascular disease. They are intended to provide clinical guidance and enable resources to be targeted in a cost effective manner. METHODS 623 patients who presented to lipid clinics across Wales had DNA testing following application of these criteria. RESULTS The proportion of patients with a pathogenic mutation ranged from 4% in those scoring 5 or less up to 85% in those scoring 15 or more. LDL-cholesterol was the strongest discriminatory factor. Scores gained from physical signs, family history, coronary heart disease, and triglycerides also showed a gradient in mutation pick-up rate according to the score. CONCLUSION These criteria provide a useful tool to guide selection of patients for DNA testing when applied by health professionals who have clinical experience of FH.

High- but not low-dose folic acid improves endothelial function in coronary artery disease

Background  While folic acid (FA) reduces plasma homocysteine (Hcy), whether the simultaneous improvement in endothelial function is dependent on Hcy lowering per se is questionable. In the present study the relationship between FA dose, Hcy lowering and endothelial function in patients with coronary artery disease (CAD) was investigated.

Vitamin C therapy ameliorates vascular endothelial dysfunction in treated patients with homocystinuria

AbstractObjectives: We sought to investigate the effects of short- and long-term vitamin C therapy on endothelial dysfunction in patients with homocystinuria. Background: Untreated homocystinuria due to cystathionine β-synthase deficiency is associated with premature atherothrombotic disease; 25% of untreated patients suffer a vascular event by the age of 16 years and 50% by 29 years. Treatment directed at reducing homocysteine accumulation significantly reduces this risk. However, despite ‘optimal’ treatment and compliance, hyperhomocysteinaemia usually persists and individuals exhibit endothelial dysfunction indicative of an adverse cardiovascular prognosis. Additional intervention is therefore required to further reduce cardiovascular risk. Methods: We investigated the endothelial effects of acute (2 g single dose) and chronic (1 g/day for 6 months) administration of oral vitamin C in 5 patients with homocystinuria (mean age 26 years, 1 male) and 5 age- and sex-matched controls. Brachial artery endothelium-dependent flow-mediated dilatation (FMD) and endothelium-independent responses to nitroglycerin (NTG) were measured using high-resolution ultrasonic vessel wall-tracking. Results:Baseline: Plasma total homocysteine was 100.8 ± 61.6 and 9.2 ± 1.9 μmol/L in the patient and control groups, respectively (p < 0.001). FMD responses were impaired in the patient group (20 ± 40 μm) compared with the controls (116 ± 30 μm) (p < 0.001). Vitamin C administration: FMD responses in the patient group improved both acutely, 160 ± 65 μm at 4 h (p < 0.001), and chronically, 170 ± 70 μm at 2 weeks (p < 0.001) and 170 ± 40 μm at 6 months (p < 0.001). FMD responses in the control group were unaltered (p = 0.526). Within both groups, neither the vascular response to NTG nor plasma homocysteine was altered (p > 0.4). Conclusions: Vitamin C ameliorates endothelial dysfunction in patients with homocystinuria, independent of changes in homocysteine concentration and should therefore be considered as an additional adjunct to therapy to reduce the potential long-term risk of atherothrombotic disease.

Reduction in plasma total homocysteine through increasing folate intake in healthy individuals is not associated with changes in measures of antioxidant activity or oxidant damage

Background: Various mechanisms have been proposed to explain the association between plasma total homocysteine (tHcy) and risk of cardiovascular disease, including oxidative activity of homocysteine.Objective: To explore the putative role of reactive oxygen species in the association between plasma tHcy and risk of cardiovascular disease in healthy individuals.Design: A double-blind, placebo-controlled crossover intervention to increase folate intake through diet (increased consumption of folate-rich foods) and supplement (400 µg folic acid) was carried out in 126 healthy men and women. Measurements were made of antioxidant activity in red blood cells and plasma, and products of oxidant damage in plasma.Results: Diet and supplement-based interventions led to an increase in measures of folate status and a reduction in plasma tHcy. This was not associated with any significant change in measures of antioxidant activity (plasma and red blood cell glutathione peroxidase activity and red blood cell superoxide dismutase activity) or oxidant damage (plasma malondialdehyde), although an improvement in plasma total antioxidant capacity just failed to reach significance.Conclusions: In healthy individuals lowering plasma tHcy does not have any functional implications regarding oxidative damage.

Folate improves endothelial function in patients with coronary heart disease

Abstract Elevated plasma homocysteine is associated with increased cardiovascular risk but it remains unproven that the effect is directly causal. Folate and homocysteine metabolism are closely linked such that administration of folic acid in doses ranging from 0.2–10 mg/day lowers plasma total homocysteine (tHcy) by up to 25%. Folic acid has been widely advocated as a therapy which may reduce cardiovascular risk, but the clinical benefit remains as yet unproven and the choice of dose remains unclear. The effect of folic acid on endothelial function has been investigated in patients with proven coronary heart disease (CHD) by measuring flow-mediated dilatation (FMD) in the brachial artery. Oral folic acid (5 mg/day) markedly enhances endothelial function (FMD) and lowers homocysteine. Studies of the acute effects of folic acid have shown that this improvement occurs within the first 2–4 hours following the first dose, at which times there was no significant reduction in plasma tHcy. Administration of 5-methyltetrahydrofolate directly into the brachial artery markedly enhances FMD, an effect that is blocked by monomethyl arginine (LNMMA), suggesting that the effects of folate are mediated by nitric oxide. This Review summarises studies which show that pharmacological doses of folate markedly enhance endothelial function in patients with CHD. The discordance with changes in plasma homocysteine suggests that these effects may occur by mechanisms distinct from homocysteine lowering.

All-cause and cardiovascular mortality in treated patients with severe hypertriglyceridaemia: A long-term prospective registry study

OBJECTIVE To examine all-cause and cardiovascular mortality in patients with severe hypertriglyceridaemia. METHODS 337 patients aged less than 80 years (47 with diabetes, 75 women) with a fasting triglyceride concentration on at least two occasions of >5.0mmol/l were registered by 21 lipid clinics in the United Kingdom and followed prospectively between 1980 and 2008 for 4353 person-years. The standardised mortality ratio (SMR) was calculated by comparison with the general population. RESULTS The mean untreated total cholesterol concentration was 9.8 (SD 3.6)mmol/l for men and 11.9 (7.2)mmol/l for women and the corresponding geometric mean triglyceride concentration was 12.6 (inter-quartile range 7.3, 21.6) and 15.7 (8.2, 29.2)mmol/l. There were 70 deaths, including 35 from CHD and 7 from stroke. The SMR for CHD was raised at 327 (95% confidence intervals 228, 455; p<0.0001) and remained elevated after excluding patients with diabetes at registration (SMR=287, 95% CI 190, 419; p<0.0001), and after excluding patients with CHD at registration (SMR=259, 95% CI 158, 400; p=0.0003). The increased SMR was most marked in younger men aged 40-59 years (SMR=544, 95% CI 304, 897; p<0.0001). The SMR for stroke for patients aged 20-79 years was raised at 262 (95% CI 105, 540; p=0.04), as was all-cause mortality at 164 (95% CI 129, 208; p<0.001). CONCLUSION Severe hypertriglyceridaemia is associated with a substantially increased mortality from cardiovascular disease, even in the absence of diabetes. In addition to lowering triglyceride concentrations to reduce the risk of pancreatitis, treatment should aim to reduce the overall cardiovascular risk.

Somatotype and angiographically determined atherosclerotic coronary artery disease in men.

The relationship between somatotype and somatotype components with coronary artery disease (CAD) and regional adiposity was considered in 58 males (age 60.2 ± 9.4 years) undergoing investigative coronary angiography for suspected atherosclerotic CAD. Severity of CAD was determined in terms of both the degree of stenosis and the anatomical position of the lesions on the coronary arteries (myocardial score). Six patients had negative angiographic findings but three of these had impaired left ventricular function as determined by left ventriculography. The mean (±SD) somatotype of the group was 5.7 / 5.6 / 1.2 (1.7 / 1.4 / 1.0), illustrating a clear dominance of the first two somatotype components. Canonical correlation analysis showed that somatotype was not significantly related to the angiography results (P > 0.05). However, correlations between the somatotype components and the angiography results with their respective first canonical variates showed that the somatotype variate was one of high mesomorphy and low ectomorphy and the angiography variate was essentially one of a high myocardial score. After adjustment for the confounding interrelationship among the somatotype components, endomorphy was significantly correlated with abdominal circumference (r = 0.65, P < 0.001), the abdomen‐to‐hip ratio (r = 0.53, P < 0.001) and the abdominal sagittal diameter (r = 0.60, P < 0.001). Mesomorphy was not related to these indicators of android or abdominal adiposity following partial adjustment. Ectomorphy was inversely related to the indices of general and regional adiposity. This study suggests that adiposity and muscularity are important features in terms of increased CAD risk, whereas linearity is beneficial. Am. J. Hum. Biol. 12:128–138, 2000.