Ariel Lant

Interpractice audit of diagnosis and management of hypertension in primary care: educational intervention and review of medical records

Abstract Objective: To determine whether peer review medical audit in a primary care setting changes clinical behaviour in relation to the management of hypertension. Design: Review of medical records in general practices to identify hypertensive patients followed up by assessment of the pre-educational and post-educational management of interventions. Setting: Six general practices in north west London picked at random within defined criteria of geography and size. Subjects: 740 hypertensive patients managed by 25 different general practitioners. Main outcome measures: Improved level of care in terms of better diagnosis by having at least three blood pressure readings before the start of drug treatment, better level of recordings of lifestyle parameters as shown by the level of recordings of body mass index and total lipid values, and better control of blood pressure and harm minimisation as shown by the level of recordings of urea and electrolyte values. Results: Improvement was noted in the level of recordings of body mass index, total lipid concentrations, and urea and electrolyte values but not in better diagnosis or blood pressure control. Conclusion: Clinical behaviour of general practitioners can be changed by peer review but more complex behavioural changes which require the cooperation of the patients and cognitive actions by the general practitioners need further investigation. Key messages Peer review can significantly change the clinical behaviour of general practitioners with respect to undertaking simple diagnostic procedures, recording lifestyle variables, and carrying out laboratory measurements Attempts to improve control of blood pressure by general practitioners is a target less easily achieved A primary care study has shown that despite an active education programme over two years the proportion of treated patients whose blood pressure was controlled to <160/90 mm Hg remained at only one third

Controversies surrounding erythrocyte sodium-lithium countertransport

Background Interest originally arose in ouabain-insensitive lithium transport across erythrocyte membranes when it was found that lithium could substitue for sodium, either undergoing 1 :1 lithium exchange or 1 :1 sodium-lithium countertransport in a manner that follows Michaelis- Menten kinetics. Elevation of the sodium-lithium countertransport activity in hypertension was first noted in 1980 and found to be a genetically linked phenomenon. This observation has since been confirmed on several occasions and associations with other dieases such as diabetes have been noted. Nevertheless, many unanswered questions remain about the clinical significance of disturbed sodium-lithium countertransport and its pathological basis. Methods Traditional methods for characterizing the sodium-lithium countertransporter have depended on determining differences between lithium fluxes into sodium-rich and sodium-free media. There have been inherent problems in deciding on suitable sodium substitutes. Of the available alternatives, choline has emerged as having advantages over magnesium. Reports in the literature have often failed to take into account varied assay conditions, making comparisons of data from different laboratories difficult A further complexity has been the realization that sodium-lithium countertransport activity incorporates two key elements in the form of Vmax and km. Kinetic studies have shown independent variation in these two parameters with various disease states. Results Much of the published work to date has continued to rely on measurement of countertransport activity, with magnesium acting as the predominant sodium-substitute. This has occurred despite the undoubted benefits obtained from kinetic analysis. Where kinetics of the sodium-lithium countertransporter have been determined, there have emerged clear associations between Vmax and environmental influences such as plasma lipids with elevated values in dyslipidaemic states including diabetes. The affinity constant, km, is more clearly under genetic control and has independent associations with vascular disease. Conclusions Study of the erythrocyte sodium-lithium countertransporter has revealed interesting relationships between altered behaviour of the transporter and specific disease states. Although still somewhat of an enigma, this transporter is emerging as an important membrane constituent whose further study may help us to understand the molecular mechanisms leading to vascular disease.

Erythrocyte sodium-lithium countertransport and blood pressure in identical twin pairs discordant for insulin dependent diabetes.

OBJECTIVE--To investigate whether insulin dependent diabetes is responsible for the abnormal behaviour of the carrier in sodium-lithium countertransport and whether the diabetic state is associated with rise in blood pressure. DESIGN--Case-control study. SETTING--London teaching hospital. SUBJECTS--44 twin pairs discordant for insulin dependent diabetes living in United Kingdom and 44 healthy control subjects matched for age, sex, and body mass index. None of the twin pairs or the controls had evidence of microalbuminuria. MAIN OUTCOME MEASURES--Sodium-lithium countertransport activity in erythrocytes and arterial blood pressure. RESULTS--The mean (95% confidence interval) sodium-lithium countertransport activity (mmol Li per litre of red blood cells per h) of the diabetic twins (0.291 (0.244 to 0.338)) was similar to that of their non-diabetic cotwins (0.247 (0.204 to 0.290)); both values were significantly higher than that of the controls (0.187 (0.157 to 0.216); p < 0.05). In addition, systolic blood pressure was higher in those twins with diabetes (127 (122 to 133) mm Hg) than in the non-diabetic cotwins (122 (117 to 127) mm Hg; p < 0.01). There were no significant differences in mean diastolic blood pressure between any of the groups studied. CONCLUSIONS--The raised erythrocyte sodium-lithium countertransport activity in the diabetic twins compared with the controls seems to be inherited rather than a consequence of overt diabetes. The higher systolic blood pressure in diabetic twins than non-diabetic cotwins indicates that insulin dependent diabetes does exert a small influence on systolic blood pressure.

The apolipoprotein E2 allele modulates activity and maximal velocity of the sodium–lithium countertransporter

BACKGROUND Alterations in erythrocyte sodium-lithium countertransport (SLC) activity and its maximal velocity (Vmax) are associated with hypertension and hypertriglyceridemia. The presence of apolipoprotein (apo) E variants is associated with hypertriglyceridemia. This study investigated the relationship between apoE phenotype and SLC kinetics. METHODS Cardiovascular risk factors and SLC kinetics were measured in 171 subjects and 69 controls. Apolipoprotein E phenotypes were determined by Western blotting. RESULTS Patients were 51% male, aged 56+/-13 years, with a blood pressure (BP) of 134+/-22/81+/-11 mm Hg, total cholesterol of 6.71+/-1.57 (256+/-61 mg/dL); median triglycerides 1.65 mmol/L (146 mg/dL) (range, 0.31 to 9.85 mmol/L; 27 to 872 mg/dL) and high-density lipoprotein (HDL) 1.39+/-0.43 mmol/L (54+/-16.6 mg/dL); fasting glucose 4.91+/-0.61 mmol/L (88.5+/-11.0 mg/dL); median insulin 11.7 IU/L (range, 3.7 to 39.8 IU/L). Phenotype frequencies were E3/E3 56%, E2/E3 14%, E2/E2 1%, E3/E4 27%, and E4/E4 2%. The SLC activity, Vmax, and sodium affinity (Km) were not significantly different with respect to apoE phenotype in simple analysis by Kruskal Wallis test. However, in multiple regression analysis after exclusion of BP, a strong co-correlate of SLC activity, the presence of an apoE2 allele was associated reduced activity (beta = -0.061; P = .01) along with HDL:apoA1 ratio (beta = -0.170; P < .001), whereas for the kinetic parameter Vmax, associations were found with triglyceride (beta = 0.029; P = .04), HDL:apoA1 ratio (beta = -0.186; P = .03) and the presence of an apoE2 allele (beta = -0.089; P = .04). CONCLUSIONS These findings suggest that the apoE phenotype may modulate SLC activity and that the presence of an apoE2 allele phenotype is associated with lower SLC activity and Vmax.

Relation between sodium–lithium countertransport and hypertriglyceridemia in type V hyperlipidemia

Sodium-lithium countertransport (SLC) kinetics were measured in 30 patients with type V hyperlipidemia, 30 patients with type IIB hyperlipidemia on similar treatment, and 30 age- and sex-matched healthy controls. Clinical and laboratory data including basic anthropometry and blood pressure were obtained and blood was taken for detailed lipid biochemistry, glucose, insulin, and leptin measurements. Patients with type V hyperlipidemia were normotensive but more obese than controls, had elevated triglycerides, very low-density lipoprotein, glucose, and insulin; and reduced HDL cholesterol compared with type IIb controls. The median SLC activity (0.23 v 0.21 mmol Li+/L RBC/h) and median maximal velocity (0.33 v 0.31 mmol Li+/L RBC/h) were increased, but not significantly, compared to controls. In patients with type V hyperlipidemia SLC maximal velocity correlated with log triglycerides (r2 = 0.853; P < .001) and log very low-density lipoprotein (VLDL) triglycerides (r2 = 0.947; P < .001). Sodium-lithium countertransport maximal velocity correlated weakly with the homeostasis model assessment index of insulin resistance (r2 = 0.224; P = .06). The sodium affinity of the transporter did not differ between the groups and was independent of any of clinical or biochemical parameter studied. We conclude that VLDL triglyceride is strongly correlated with SLC maximal velocity and activity in patients with type V hyperlipidemia.

Kinetic Characteristics of the Erythrocyte Sodium-Lithium Countertransporter in Subjects with Coronary Artery Disease

Sodium-lithium countertransport activity, external affinity for sodium (kNa) and maximal rate of turnover (Vmax), were characterized in 21 male subjects (aged 45 to 65 years) with angiographically proven coronary artery disease; these were compared with a matched group of healthy controls. No significant differences in countertransport activity were noted between the coronary artery disease patients and the healthy controls. By contrast, the median [range] kNa in the coronary artery disease group (8.5 [2.6 to 30.5] mmol/L Na) was significantly lower than that in the controls (59.9 [5.9 to 240.5] mmol/L Na; P < .0001). This reduction was accompanied by a significantly lower mean Vmax (controls 0.403 +/- 0.187 v coronary artery disease group 0.248 +/- 0.121 mmol Li/L RBC/h; P < .01). The findings suggest that disturbed behavior of the sodium-lithium countertransporter is not confined to hypertension but may represent a broader-based membrane dysfunction associated with vascular disease.

Kinetic characteristics of the erythrocyte sodium-lithium countertransporter in black normotensive subjects compared with three other ethnic groups

Sodium-lithium countertransport activity has been proposed as a marker for hypertension and is lower in black compared to Caucasian subjects both with and without vascular disease. The question arises of what is the primary kinetic locus of the altered behaviour of the countertransporter in black subjects and whether this is also seen in normotensive subjects from other non-Caucasian ethnic groups. We studied the sodium-lithium countertransporter in four ethnic groups (black [n = 45], Caucasian [n = 45], Chinese [n = 40], and South Asian [n = 39]) of age-matched normotensive males (age range 18–35 y) with no first-degree family history of hypertension or diabetes. The clinical and laboratory characteristics of the subjects were similar in all four ethnic groups. Minor differences noted were: significantly higher mean height, weight and serum creatinine concentration (P < 0.001) and significantly lower plasma triglyceride concentration (P = 0.02) in the black compared to the other study groups. Sodium-lithium countertransport activity (mmol Li/l RBC h) was significantly lower in the black subjects (0.113 [0.013–0.265]) compared with the other groups (Caucasian, 0.247 [0.037–0.614]; Chinese, 0.210 [0.100–0.707]; South Asian, 0.211 [0.037–0.617]; P < 0.001). no differences were noted between the four study groups in respect of kNa. Mean (s.d.) Vmax values (mmol Li/l RBC h) were also reduced in the black subjects (0.152 [0.088]) compared to the other ethnic groups (Caucasian, 0.376 [0.159]; Chinese, 0.364 [0.182]; South Asian, 0.329 [0.155]; P < 0.001) and there was a strong relationship between countertransport activity and vmax (r > 0.52; P < 0.001; for each of the study groups). the differences in mean vmax noted between the Caucasian, South Asian and Chinese subjects were not significant.These results show that, when compared with three other selected ethnic groups, black subjects demonstrate an altered behaviour with respect to Vmax of the sodium-lithium countertransporter, which occurs in the absence of demonstrable vascular pathology.

Effects of lipids in patients with familial hypercholesterolaemia on the kinetics of the sodium-lithium countertransporter

Sodium-lithium countertransport kinetics were measured in 87 patients (50 male; 37 female) with heterozygous familial hypercholesterolaemia (FH) and a group of 38 age range and sex-distribution matched controls. Basic clinical data including basic anthropometry, blood pressure were obtained and blood was taken for detailed lipid biochemistry, glucose and insulin measurement. Patients with FH had elevated total cholesterol, low-density lipoprotein (LDL)-cholesterol and apolipoprotein B concentrations compared to controls. The activity and log transformed maximal velocity (Vmax) of the sodium-lithium countertransporter unlike the affinity (Km) were reduced in patients with FH compared to controls (geometric means 0.172 vs 0.217 mmol Li+/L.RBC.hr; P = 0.02; 0.237 vs0.317 mmol Li+/L.RBC.hr; P = 0.009 respectively). In multiple regression analysis, log normalised SLC activity correlated weakly with log triglyceride (β = 0.225; P = 0.06) and cholesterol (β = −0.112 P = 0.06). Log Vmaxcorrelated with log triglyceride (β = 0.307; P = 0.02), and high-density lipoprotein (HDL) (β = 0.74; P = 0.03) whilst Km correlated with HDL (β = 1.73; P < 0.001) and apoai (β = −1.76; P = 0.0048), LDL (β = −0.14; P = 0.05), and creatine kinase (β = 0.003; P = 0.01). Cholesterol and triglyceride concentrations rather than insulin resistance seem to be the key features affecting the environmental alteration of sodium lithium countertransporter Vmax in patients with familial hypercholesterolaemia.