Christopher A. R. Sainsbury

Implications of discoveries from genome-wide association studies in current cardiovascular practice

Genome-wide association studies (GWAS) have identified several genetic variants associated with coronary heart disease (CHD), and variations in plasma lipoproteins and blood pressure (BP). Loci corresponding to CDKN2A/CDKN2B/ANRIL, MTHFD1L, CELSR2, PSRC1 and SORT1 genes have been associated with CHD, and TMEM57, DOCK7, CELSR2, APOB, ABCG5, HMGCR, TRIB1, FADS2/S3, LDLR, NCAN and TOMM40-APOE with total cholesterol. Similarly, CELSR2-PSRC1-SORT1, PCSK9, APOB, HMGCR, NCAN-CILP2-PBX4, LDLR, TOMM40-APOE, and APOC1-APOE are associated with variations in low-density lipoprotein cholesterol levels. Altogether, forty, forty three and twenty loci have been associated with high-density lipoprotein cholesterol, triglycerides and BP phenotypes, respectively. Some of these identified loci are common for all the traits, some do not map to functional genes, and some are located in genes that encode for proteins not previously known to be involved in the biological pathway of the trait. GWAS have been successful at identifying new and unexpected genetic loci common to diseases and traits, thus rapidly providing key novel insights into disease biology. Since genotype information is fixed, with minimum biological variability, it is useful in early life risk prediction. However, these variants explain only a small proportion of the observed variance of these traits. Therefore, the utility of genetic determinants in assessing risk at later stages of life has limited immediate clinical impact. The future application of genetic screening will be in identifying risk groups early in life to direct targeted preventive measures.

Growth hormone replacement reduces C-reactive protein and large-artery stiffness but does not alter endothelial function in patients with adult growth hormone deficiency.

Hypopituitary patients have an increased risk of vascular mortality that may relate to growth hormone deficiency (GHD). We investigated the effects of 6 months of GH therapy on large‐ and small‐artery function and high‐sensitivity C‐reactive protein (hsCRP) in a cohort of GH‐deficient patients. Sixteen hypopituitary patients were randomized to 6 months of GH therapy or no treatment, then vice versa. hsCRP, 24‐h blood pressure (BP) and pulse wave velocity (PWV) were measured and resistance arteries were used to construct concentration–response curves to endothelium‐dependent and ‐independent agents. GH therapy increased IGF‐1 from 60 ± 7·2 to 167 ± 16·2 µg/l [confidence interval (CI) 94·9, 138·8, P < 0·001]. hsCRP declined after 6 months of GH from 3·8 ± 0·88 to 2·0 ± 0·49 mg/l (CI 0·73, 3·57, P = 0·006). Mean arterial BP fell from 91·7 ± 1·5 to 89·3 ± 1·2 mmHg (CI 0·81, 4·07, P = 0·005), as did PWV (8·1 ± 0·4 to 6.7 ± 0·5 m/s). The decline in PWV correlated with the decline in hsCRP (r = 0·68, P = 0·01). Resistance artery function was unchanged after GH therapy. GH replacement may lead to differentially altered production of vasorelaxant agents from the endothelium of large and small arteries. Reduction in vascular inflammation may be associated with reduced vascular risk.

Non-esterified fatty acids impair endothelium-dependent vasodilation in rat mesenteric resistance vessels.

Elevated circulating levels of NEFAs (non-esterified fatty acids) are associated with states of insulin resistance and increased risk of vascular disease. Previous animal and human studies have demonstrated NEFA-induced endothelial dysfunction of large conduit arteries, reversible by the antioxidant ascorbic acid. We therefore investigated the effect of NEFAs on carbachol-induced endothelium-dependent vasodilation of rat resistance arteries in vitro using the technique of wire myography. In addition, we investigated the effect of co-incubation of NEFAs and ascorbic acid. Cumulative concentration-response curves to carbachol (endothelium-dependent vasodilation) and SNAP (S-nitroso-N-acetyl-DL-penicillamine; endothelium-independent vasodilation) were constructed. Those to carbachol were repeated following a 30 min incubation with either oleic acid (10(-4) M) or palmitic acid (10(-4) M), demonstrating significant impairment of endothelium-dependent vasodilation with both [P<0.05, comparison of pD2 values (the negative log concentration of agonist required to effect a 50% response)]. A cumulative concentration-response curve to carbachol was repeated following co-incubation with palmitic acid (10(-4) M) and the antioxidant ascorbic acid (10(-5) M), demonstrating an abolition of the previously observed endothelial dysfunction induced by palmitic acid. There was no impairment of vasodilation to SNAP following NEFA incubation. We conclude that NEFAs directly impair endothelial function in rat resistance arteries via an increase in oxidative stress at the vascular endothelium.

Trends in recorded capillary blood glucose and hypoglycaemia in hospitalised patients with diabetes

AIMS To utilise whole-system analysis of capillary glucose measurement results to examine trends in timing of glucose monitoring, and to investigate whether these timings are appropriate based on observed patterns of hypoglycaemia. METHODS Near-patient capillary blood glucose results from eight acute hospitals collected over 57 months were analysed. Analysis of frequency of measurement, and measurements in the hypoglycaemic (<4mmol/l) and severe hypoglycaemic (<2.5mol/l) range per time of day was made. RESULTS 3345241 capillary glucose measurements were analysed. 1657594 capillary blood glucose values were associated with 106624 admissions in those categorised as having diabetes. Large peaks in frequency of glucose measurements occurred before meals, with the highest frequency of capillary glucose measurement activity being seen pre-breakfast. Overnight, an increase in measurement activity was seen each hour. This pattern was mirrored by frequency of measured hypoglycaemia. 27968 admissions (26.2%) were associated with at least one hypoglycaemic measurement. A greater proportion of measurements were within the hypoglycaemic range overnight with 61.7% of all hypoglycaemia between 2100 and 0900h, with peak risk of measured capillary glucose being hypoglycaemic between 0300 and 0400h. CONCLUSIONS Hypoglycaemic is common with the greatest risk of hypoglycaemia overnight and a peak percentage of all readings taken being in the hypoglycaemic range between 0300 and 0400h. Measurement activity overnight was driven by routine, with patterns of proportion of measurements in the hypoglycaemic range indicating that there may be a significant burden of undiscovered hypoglycaemia in the patients not routinely checked overnight.

Inpatient Glycemic Variability and Long-Term Mortality in Hospitalized Patients with Type 2 Diabetes

AIMS/HYPOTHESIS To determine the association between inpatient glycemic variability and long-term mortality in patients with type 2 diabetes mellitus. METHODS Capillary blood glucose (CBG) of inpatients from 8 hospitals was analysed. 28,353 admissions identified were matched for age, duration of diabetes and admission and median and interquartile range of CBG. 6year mortality was investigated for (i) those with CBG IQR in the top half of all IQR measurements (matched for all except IQR), vs those in the lower half and (ii) those with the lowest quartile median glucose (matched for all except median). RESULTS CONCLUSION: Higher inpatient glycemic variability is associated with increased mortality on long-term follow up. When matched by IQR, we have demonstrated higher median CBG is associated with lower long-term mortality. CBG variability may increase cardiovascular morbidity by increasing exposure to hypoglycaemia or to variability per se. In hospitalized patients with diabetes, glycemic variability should be minimised and when greater CBG variability is unavoidable, a less stringent CBG target considered.

Endothelium-dependent relaxation is resistant to inhibition of nitric oxide synthesis, but sensitive to blockade of calcium-activated potassium channels in essential hypertension

In human essential hypertension (EH), endothelium-dependent relaxation can occur independent of nitric oxide (NO) and prostacyclin (PGI2). Recent in vivo data suggest that rapid compensatory upregulation of endothelial cytochrome P450 epoxygenase 2C9 occurs to preserve vasorelaxation under conditions of decreased NO bioavailability. As one of the vascular actions of CYP2C9 is to modulate small and intermediate conductance endothelial calcium-activated potassium channels (SKCa and IKCa), we examined whether endothelium-dependent relaxation is sensitive to inhibitors of these channels (apamin and charybdotoxin) in resistance-sized vessels from human with EH. Subcutaneous gluteal biopsies were performed on 12 humans with EH and 12 matched control subjects. Resistance arteries were dissected and relaxation responses to carbachol were assessed ex vivo using wire myography in the presence of: (i) NG-nitro-L-arginine (L-NOARG)/indomethacin; and (ii) apamin/charybdotoxin. Maximal carbachol relaxation was impaired in EH vs control subjects. No differences in responses were observed with the endothelium-independent agonist, S-nitroso-N-acetyl-penicillamine. Relaxation to carbachol was attenuated following incubation with L-NOARG/indomethacin in vessels from control subjects (P<0.01 analysis of variance (ANOVA)), but not in vessels from patients with EH. The reverse pattern was seen following apamin/charybdotoxin with carbachol relaxation attenuated only in EH vessels (P<0.001 ANOVA). Endothelium-dependent relaxation is resistant to endothelial nitric oxide synthase inhibition but sensitive to blockade of calcium-activated potassium channels in human EH. Studies with more specific inhibitors are required to determine whether this response is mediated by endothelial potassium channel subtypes (SKCa and IKCa).

Comment on ‘A justification for less restrictive guidelines on the use of metformin in stable chronic renal failure’

We read with interest the article by Adam and O’Brien [1] on the use of metformin in stable chronic renal failure. Whilst we agree that lactic acidosis is a very rare complication that should not restrict metformin usage unnecessarily, we feel that using lower doses of metformin to achieve predicted plasma metformin levels of < 10 mg/l cannot be justified. In patients with estimated glomerular filtration rates of 10–19 ml/min a dose of 500 mg is recommended. Whilst it may be safe to use this dose of metformin, it is unlikely to be effective in lowering glucose. There is no evidence that efficacy of metformin is related to plasma levels of the drug. Intravenous metformin has no effect on fasting glucose, C-peptide or insulin levels, hepatic glucose production or peripheral glucose disposal [2,3]. Recent evidence suggests that metformin action is modulated by lower gut delivery and therefore dose delivery to this area and not plasma concentration predicts hypoglycaemic efficacy [4]. This would of course mean that in patients with renal insufficiency, despite metformin plasma levels being equivalent with lower dosing, that efficacy would be impaired or absent. We therefore do not think that the use of low-dose metformin in renal failure is justified.

A Practical Approach to Glucose Abnormalities in Cystic Fibrosis

Cystic fibrosis is a common genetic condition and abnormal glucose handling leading to cystic fibrosis-related diabetes (CFRD) is a frequent comorbidity. CFRD is mainly thought to be the result of progressive pancreatic damage resulting in beta cell dysfunction and loss of insulin secretion. Whilst Oral Glucose Tolerance Testing is still recommended for diagnosing CFRD, the relationship between glucose abnormalities and adverse outcomes in CF is complex and occurs at stages of dysglycaemia occurring prior to diagnosis of diabetes by World Health Organisation criteria. Insulin remains the mainstay of treatment of CF-related glucose abnormalities but the timing of insulin commencement, optimum insulin regime and targets of glycaemic control are not clear. These complexities are compounded by common issues with nutritional status, need for enteral feeding, steroid use and high disease burden on CF patients.

HbA1c variability is associated with increased mortality and earlier hospital admission in people with Type 1 diabetes

Despite evidence of morbidity, no evidence exists on the relationship between HbA1c variability and mortality in Type 1 diabetes. We performed an observational study to investigate whether the association between HbA1c variability and mortality exists in a population of people with Type 1 diabetes. As a secondary outcome, we compared onset of first hospital admission between groups.

Structured education using Dose Adjustment for Normal Eating (DAFNE) reduces long-term HbA1c and HbA1c variability

Previous evidence has demonstrated that participation in the Dose Adjustment for Normal Eating (DAFNE) education programme can reduce HbA1c and severe hypoglycaemia in people with Type 1 diabetes. In a number of studies, increased HbA1c variability has been associated with higher diabetic morbidity and mortality. No studies have examined the impact of structured education on HbA1c variability in Type 1 diabetes.