Self-rated health scores predict mortality among people with type 2 diabetes differently across three different country groupings: findings from the ADVANCE and ADVANCE-ON trials.

AIMS: To explore whether there is a different strength of association between self-rated health and all-cause mortality in people with type 2 diabetes across three country groupings: nine countries grouped together as 'established market economies'; Asia; and Eastern Europe. METHODS: The ADVANCE trial and its post-trial follow-up were used in this study, which included 11 140 people with type 2 diabetes from 20 countries, with a median follow-up of 9.9 years. Self-rated health was reported on a 0-100 visual analogue scale. Cox proportional hazard models were fitted to estimate the relationship between the visual analogue scale score and all-cause mortality, controlling for a range of demographic and clinical risk factors. Interaction terms were used to assess whether the association between the visual analogue scale score and mortality varied across country groupings. RESULTS: The visual analogue scale score had different strengths of association with mortality in the three country groupings. A 10-point increase in visual analogue scale score was associated with a 15% (95% CI 12-18) lower mortality hazard in the established market economies, a 25% (95% CI 21-28) lower hazard in Asia, and an 8% (95% CI 3-13) lower hazard in Eastern Europe. CONCLUSIONS: Self-rated health appears to predict 10-year all-cause mortality for people with type 2 diabetes worldwide, but this relationship varies across groups of countries.

Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials.

BACKGROUND: Genetic variants have been associated with the risk of coronary heart disease. In this study, we tested whether or not a composite of these variants could ascertain the risk of both incident and recurrent coronary heart disease events and identify those individuals who derive greater clinical benefit from statin therapy. METHODS: A community-based cohort study (the Malmo Diet and Cancer Study) and four randomised controlled trials of both primary prevention (JUPITER and ASCOT) and secondary prevention (CARE and PROVE IT-TIMI 22) with statin therapy, comprising a total of 48,421 individuals and 3477 events, were included in these analyses. We studied the association of a genetic risk score based on 27 genetic variants with incident or recurrent coronary heart disease, adjusting for traditional clinical risk factors. We then investigated the relative and absolute risk reductions in coronary heart disease events with statin therapy stratified by genetic risk. We combined data from the different studies using a meta-analysis. FINDINGS: When individuals were divided into low (quintile 1), intermediate (quintiles 2-4), and high (quintile 5) genetic risk categories, a significant gradient in risk for incident or recurrent coronary heart disease was shown. Compared with the low genetic risk category, the multivariable-adjusted hazard ratio for coronary heart disease for the intermediate genetic risk category was 1·34 (95% CI 1·22-1·47, p<0·0001) and that for the high genetic risk category was 1·72 (1·55-1·92, p<0·0001). In terms of the benefit of statin therapy in the four randomised trials, we noted a significant gradient (p=0·0277) of increasing relative risk reductions across the low (13%), intermediate (29%), and high (48%) genetic risk categories. Similarly, we noted greater absolute risk reductions in those individuals in higher genetic risk categories (p=0·0101), resulting in a roughly threefold decrease in the number needed to treat to prevent one coronary heart disease event in the primary prevention trials. Specifically, in the primary prevention trials, the number needed to treat to prevent one such event in 10 years was 66 in people at low genetic risk, 42 in those at intermediate genetic risk, and 25 in those at high genetic risk in JUPITER, and 57, 47, and 20, respectively, in ASCOT. INTERPRETATION: A genetic risk score identified individuals at increased risk for both incident and recurrent coronary heart disease events. People with the highest burden of genetic risk derived the largest relative and absolute clinical benefit from statin therapy. FUNDING: National Institutes of Health.

Prediction of 10-year vascular risk in patients with diabetes: the AD-ON risk score.

AIMS: To formulate a combined cardiovascular risk score in diabetes that could be useful both to physicians and healthcare funders. METHODS: Data were derived from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation Observational (ADVANCE-ON) study, a randomized controlled trial (mean duration 5 years) with a post-randomization follow-up (mean 4.9 years), that included 11 140 high-risk patients with diabetes. The outcome analysed was the occurrence of either fatal or non-fatal macrovascular or renal disease. A Cox regression model was used to determine weightings in the risk score. The resultant score was recalibrated to each of three major global regions, as covered by the ADVANCE-ON study. RESULTS: Over a median of 9.9 years, 1145 patients experienced at least one component of the combined outcome event. The resultant score, the AD-ON risk score, incorporated 13 demographic or clinical variables. Its discrimination was modest [c-statistic = 0.668 (95% confidence interval 0.651, 0.685)] but its calibration was excellent (predicted and observed risks coincided well, within disparate global regions). In terms of the integrated discrimination improvement index, its performance was marginally superior, over a 10-year risk horizon, to existing risk scores in clinical use, from a restricted version of the same data, for macrovascular and renal disease separately. CONCLUSIONS: The AD-ON risk score has advantages over the existing vascular risk scores in diabetes that used data from the original ADVANCE trial, which treat macrovascular and renal diseases separately. These advantages include its simplicity of use and global application.

The influence of physical activity on vascular complications and mortality in patients with type 2 diabetes mellitus.

AIMS: There is limited evidence regarding the association between physical activity and vascular complications, particularly microvascular disease, in patients with type 2 diabetes. METHODS: From the 11 140 patients in the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron modified release Controlled Evaluation) trial, the effect of physical activity, categorized as none, mild, moderate or vigorous, and the number of sessions within a week, was examined in multivariable regression models adjusted for potential confounders. The study end-points were major cardiovascular events, microvascular complications and all-cause mortality. RESULTS: Forty-six percent of participants reported undertaking moderate to vigorous physical activity for >15 min at least once in the previous week. During a median of 5 years of follow-up, 1031 patients died, 1147 experienced a major cardiovascular event and 1136 a microvascular event. Compared to patients who undertook no or mild physical activity, those reporting moderate to vigorous activity had a decreased risk of cardiovascular events (HR: 0.78, 95% CI: 0.69-0.88, p < 0.0001), microvascular events (HR: 0.85, 95% CI: 0.76-0.96, p = 0.010) and all-cause mortality (HR: 0.83, 95% CI: 0.73-0.94, p = 0.0044). CONCLUSIONS: Moderate to vigorous, but not mild, physical activity is associated with a reduced incidence of cardiovascular events, microvascular complications and all-cause mortality in patients with type 2 diabetes.

Resting heart rate and the risk of death and cardiovascular complications in patients with type 2 diabetes mellitus.

AIMS/HYPOTHESIS: An association between resting heart rate and mortality has been described in the general population and in patients with cardiovascular disease. There are, however, few data exploring this relationship in patients with type 2 diabetes mellitus. The current study addresses this issue. METHODS: The relationship between baseline resting heart rate and all-cause mortality, cardiovascular death and major cardiovascular events (cardiovascular death, non-fatal myocardial infarction or non-fatal stroke) was examined in 11,140 patients who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) Study. RESULTS: A higher resting heart rate was associated with a significantly increased risk of all-cause mortality (fully adjusted HR 1.15 per 10 bpm [95% CI 1.08, 1.21], p<0.001), cardiovascular death and major cardiovascular outcomes without adjustment and after adjusting for age and sex and multiple covariates. The increased risk associated with a higher baseline resting heart rate was most obvious in patients with previous macrovascular complications (fully adjusted HR for death 1.79 for upper [mean 91 bpm] vs lowest [mean 58 bpm] fifth of resting heart rate in this subgroup [95% CI 1.28, 2.50], p = .001). CONCLUSIONS/INTERPRETATION: Among patients with type 2 diabetes, a higher resting heart rate is associated with an increased risk of death and cardiovascular complications. It remains unclear whether a higher heart rate directly mediates the increased risk or is a marker for other factors that determine a poor outcome.

Association of HbA1c levels with vascular complications and death in patients with type 2 diabetes: evidence of glycaemic thresholds.

AIMS/HYPOTHESIS: There is conflicting evidence regarding appropriate glycaemic targets for patients with type 2 diabetes. Here, we investigate the relationship between HbA(1c) and the risks of vascular complications and death in such patients. METHODS: Eleven thousand one hundred and forty patients were randomised to intensive or standard glucose control in the Action in Diabetes and Vascular disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Glycaemic exposure was assessed as the mean of HbA(1c) measurements during follow-up and prior to the first event. Adjusted risks for each HbA(1c) decile were estimated using Cox models. Possible differences in the association between HbA(1c) and risks at different levels of HbA(1c) were explored using linear spline models. RESULTS: There was a non-linear relationship between mean HbA(1c) during follow-up and the risks of macrovascular events, microvascular events and death. Within the range of HbA(1c) studied (5.5-10.5%), there was evidence of 'thresholds', such that below HbA(1c) levels of 7.0% for macrovascular events and death, and 6.5% for microvascular events, there was no significant change in risks (all p > 0.8). Above these thresholds, the risks increased significantly: every 1% higher HbA(1c) level was associated with a 38% higher risk of a macrovascular event, a 40% higher risk of a microvascular event and a 38% higher risk of death (all p < 0.0001). CONCLUSIONS/INTERPRETATION: In patients with type 2 diabetes, HbA(1c) levels were associated with lower risks of macrovascular events and death down to a threshold of 7.0% and microvascular events down to a threshold of 6.5%. There was no evidence of lower risks below these levels but neither was there clear evidence of harm.

Weight changes and their predictors amongst 11 140 patients with type 2 diabetes in the ADVANCE trial.

AIMS: To determine the baseline characteristics and glucose-lowering therapies associated with weight change among patients with type 2 diabetes. METHODS: Eleven thousand one hundred and forty participants in the ADVANCE trial were randomly assigned to an intensive [aiming for a haemoglobin A1c (HbA1c) ≤6.5%] or a standard blood glucose-control strategy. Weight was measured at baseline and every 6 months over a median follow-up of 5 years. Multivariable linear regression and linear-mixed effect models were used to examine predictors of weight change. RESULTS: The mean difference in weight between the intensive and standard glucose-control arm during follow-up was 0.75 kg (95% CI: 0.56-0.94), p-value <0.001. The mean weight decreased by 0.70 kg (95% CI: 0.53-0.87), p < 0.001 by the end of follow-up in the standard arm but remained stable in the intensive arm, with a non-significant gain of 0.16 kg (95% CI: -0.02 to 0.34), p = 0.075. Baseline factors associated with weight gain were younger age, higher HbA1c, Caucasian ethnicity and number of glucose-lowering medications. Treatment combinations including insulin [3.22 kg (95% CI: 2.92-3.52)] and thiazolidinediones [3.06 kg (95% CI: 2.69-3.43)] were associated with the greatest weight gain while treatment combinations including sulphonylureas were associated with less weight gain [0.71 kg (95%CI: 0.39-1.03)]. CONCLUSIONS: Intensive glucose-control regimens are not necessarily associated with substantial weight gain. Patient characteristic associated with weight change were age, ethnicity, smoking and HbA1c. The main treatment strategies predicting weight gain were the use of insulin and thiazolidinediones.

Metabolic syndrome, impaired fasting glucose and obesity, as predictors of incident diabetes in 14 120 hypertensive patients of ASCOT-BPLA: comparison of their relative predictability using a novel approach.

AIMS: To evaluate, in hypertensive patients, whether the metabolic syndrome is a better predictor of new-onset diabetes compared with impaired fasting glucose, obesity or its other individual components alone, or collectively. METHODS: Cox models were developed to assess the risk of new-onset diabetes associated with the metabolic syndrome after adjusting for a priori confounders (age, sex, ethnicity and concomitant use of non-cardiovascular medications), its individual components and other determinants of new-onset diabetes. Area under receiver operator curves using the metabolic syndrome or models of impaired fasting glucose were compared, and the ability of these models to correctly identify those who (after 5-years of follow-up) would or would not develop diabetes was assessed. RESULTS: The metabolic syndrome adjusted for a priori confounders and its individual components, and further adjusted for other determinants, was associated with significantly increased risk of new-onset diabetes [1.19 (1.00-1.40), P = 0.05 and 1.22 (1.03-1.44), P = 0.02, respectively]. The discriminative ability of the metabolic syndrome model [area under receiver operating curve: 0.764 (0.750-0.778)] was significantly better than the model of impaired fasting glucose [0.742 (0.727-0.757)] (P < 0.001). The metabolic syndrome correctly allocates the risk of new-onset diabetes in a significantly higher proportion of patients (62.3%) than impaired fasting glucose status (37.7%) (P < 0.001). The presence of both the metabolic syndrome and impaired fasting glucose were associated with an approximately 9-fold (7.47-10.45) increased risk of new-onset diabetes. Among normoglycaemic patients, the metabolic syndrome was also associated with significantly increased risk of new-onset diabetes, after adjusting for BMI and a priori confounders [1.66 (1.29-2.13)]. CONCLUSIONS: Both impaired fasting glucose and the metabolic syndrome predict the risk of new-onset diabetes; however, the metabolic syndrome is a better predictor than impaired fasting glucose in assigning the risk of new-onset diabetes in hypertensive patients, and among those with normoglycaemia.

Oral disease and subsequent cardiovascular disease in people with type 2 diabetes: a prospective cohort study based on the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) trial.

AIMS/HYPOTHESIS: While there are plausible biological mechanisms linking oral health with cardiovascular disease (CVD) and mortality rates, no study, to our knowledge, has examined this association in a representative population of people with type 2 diabetes. METHODS: We used the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) study, a large, detailed, randomised controlled trial among a general population of individuals with type 2 diabetes. For the purposes of the present analyses, data from the trial are used within a prospective cohort study design. A total of 10,958 men and women, aged 55 to 88 years and with type 2 diabetes, participated in a baseline medical examination, during which they counted their number of natural teeth and reported the number of days that their gums had bled over the preceding year. Study members were followed up for mortality and morbidity over 5 years. RESULTS: After controlling for a range of potential confounding factors, the group with no teeth had a markedly increased risk of death due to all causes (HR 1.48, 95% CI 1.24-1.78), CVD (1.35, 1.05-1.74) and non-CVD (1.64, 1.26-2.13), relative to the group with the most teeth (≥22 teeth). Frequency of bleeding gums was not associated with any of the outcomes of interest. There was no suggestion that treatment group or sex modified these relationships. CONCLUSIONS/INTERPRETATION: In people with type 2 diabetes, oral disease, as indexed by fewer teeth, was related to an increased risk of death from all causes and of death due to CVD and non-CVD.

Association between alcohol consumption and diabetic retinopathy and visual acuity-the AdRem Study.

AIMS: We investigated the association between alcohol consumption and diabetic retinopathy and deterioration of visual acuity in individuals with Type 2 diabetes. METHODS: We conducted a cohort analysis of 1239 participants with Type 2 diabetes aged 55-81 years enrolled in the AdRem study, a sub-study of the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial. Current and past consumption of wine, spirits and beer was measured by self-report. Moderate and heavy alcohol consumption was defined as 1-14 and >14 drinks/week, respectively. Diabetic retinopathy, measured by mydriatic stereoscopic seven-field retinal photography, was defined by a 2-step progression in the Early Treatment of Diabetic Retinopathy Study (ETDRS) score or the presence of any retinal vascular lesions. Deterioration of visual acuity was defined by a decrease of two lines in best vision in either eye, measured corrected, or through a pinhole using a Snellen chart. RESULTS: In a mean follow-up of 5.5 years, we identified 182 participants with a 2-step progression in the ETDRS score, 640 participants with the presence of any retinal vascular lesions and 693 participants with a deterioration of visual acuity. Current moderate consumption of alcohol, compared with no current consumption, was not associated with presence or progression of diabetic retinopathy; however, it was associated with higher risk of deterioration of visual acuity (multivariable-adjusted OR 1.83; 95% CI 1.34-2.48; P<0.001). CONCLUSIONS: Alcohol consumption is associated with increased risk of deterioration of visual acuity, but not with retinopathy in individuals with Type 2 diabetes.

The economic consequences of non-adherence to lipid-lowering therapy: results from the Anglo-Scandinavian-Cardiac Outcomes Trial.

BACKGROUND: Adherence to lipid-lowering therapy in clinical practice is less than ideal. Analysis of registry data has indicated that this is associated with poor outcomes. The objective of the present analysis was to assess the impact of high adherence to drug (defined as > 80% of days covered), compared with low adherence to drug (< 50% of days covered) in terms of risk of events and long-term economic consequences. DESIGN: Open-label follow up of a randomised placebo-controlled trial in hypertensive patients. METHODS: Cox proportional hazards and Poisson regression models were used to assess the hazard ratio of patients with high adherence compared with low adherence while controlling for cardiovascular risk. A Markov model was used to predict the long-term costs and health outcomes associated with poor adherence during the follow-up period. RESULTS: Both statistical models indicated that high adherence is associated with improved prognosis [Cox model: 0.75; 95% confidence interval (CI): 0.56-0.98, Poisson model hazard ratio: 0.73; 95% CI: 0.58-0.98]. Discounted at 3.5% per year, the Markov model predicts that as a consequence of higher adherence during the follow-up period, costs would be higher (1689 pounds per patient compared with 1323 pounds per patient) because of higher drug costs, but the projected survival and quality-adjusted survival (QALY) would also be longer (10.83 compared with 10.81 life years and 8.13 compared with 8.11 QALYs). CONCLUSION: Given the higher risk of cardiovascular events associated with low adherence shown here, measures to improve adherence are an important part of the prevention of cardiovascular disease.

Cognitive function and risks of cardiovascular disease and hypoglycaemia in patients with type 2 diabetes: the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial.

AIMS/HYPOTHESIS: The relationship between cognitive function, cardiovascular disease and premature death is not well established in patients with type 2 diabetes. We assessed the effects of cognitive function in 11,140 patients with type 2 diabetes who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Furthermore, we tested whether level of cognitive function altered the beneficial effects of the BP-lowering and glycaemic-control regimens in the trial. METHODS: Cognitive function was assessed using the Mini Mental State Examination at baseline, and defined by scores 28-30 ('normal', n = 8,689), 24-27 ('mild dysfunction', n = 2,231) and <24 ('severe dysfunction', n = 212). Risks of major cardiovascular events, death and hypoglycaemia and interactions with treatment were assessed using Cox proportional hazards analysis. RESULTS: Relative to normal function, both mild and severe cognitive dysfunction significantly increased the multiple-adjusted risks of major cardiovascular events (HR 1.27, 95% CI 1.11-1.46 and 1.42, 95% CI 1.01-1.99; both p < 0.05), cardiovascular death (1.41, 95% CI 1.16-1.71 and 1.56, 95% CI 0.99-2.46; both p

Effects of HIV status and antiretroviral therapy on blood pressure.

OBJECTIVE: High blood pressure is a major risk factor for cardiovascular disease and concerns have been raised over its possible association with antiretroviral drugs. The objective of this study was to explore the associations among blood pressure, HIV status and two predefined highly active antiretroviral therapy (HAART) regimens: treatment with and without nonnucleoside reverse transcriptase inhibitors (NNRTIs) (NNRTI- and non-NNRTI-based HAART). METHOD: A cross-sectional survey was conducted among 612 adults attending the Sexual Health Outpatient Department at St Mary's NHS Hospital Trust, London. RESULTS: HIV-infected patients treated with NNRTIs had a blood pressure that was 4.6/4.2 mmHg higher than those who were HIV positive but treatment naïve. The diastolic difference remained statistically significant after adjusting for potential confounders of this association (2.4 mmHg; P=0.03). There was no difference in blood pressure between those treated with non-NNRTI-based regimens and those who were HIV positive but treatment naïve. CONCLUSION: NNRTIs may be associated with an increase in blood pressure. Pending further more robust evidence from randomized clinical trials it would be prudent for clinicians to monitor blood pressure in all HIV-infected patients, particularly after initiating treatment with NNRTIs, and to commence antihypertensive therapy whenever appropriate.

Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial.

BACKGROUND: Blood pressure is an important determinant of the risks of macrovascular and microvascular complications of type 2 diabetes, and guidelines recommend intensive lowering of blood pressure for diabetic patients with hypertension. We assessed the effects of the routine administration of an angiotensin converting enzyme (ACE) inhibitor-diuretic combination on serious vascular events in patients with diabetes, irrespective of initial blood pressure levels or the use of other blood pressure lowering drugs. METHODS: The trial was done by 215 collaborating centres in 20 countries. After a 6-week active run-in period, 11 140 patients with type 2 diabetes were randomised to treatment with a fixed combination of perindopril and indapamide or matching placebo, in addition to current therapy. The primary endpoints were composites of major macrovascular and microvascular events, defined as death from cardiovascular disease, non-fatal stroke or non-fatal myocardial infarction, and new or worsening renal or diabetic eye disease, and analysis was by intention-to-treat. The macrovascular and microvascular composites were analysed jointly and separately. This trial is registered with ClinicalTrials.gov, number NCT00145925. FINDINGS: After a mean of 4.3 years of follow-up, 73% of those assigned active treatment and 74% of those assigned control remained on randomised treatment. Compared with patients assigned placebo, those assigned active therapy had a mean reduction in systolic blood pressure of 5.6 mm Hg and diastolic blood pressure of 2.2 mm Hg. The relative risk of a major macrovascular or microvascular event was reduced by 9% (861 [15.5%] active vs 938 [16.8%] placebo; hazard ratio 0.91, 95% CI 0.83-1.00, p=0.04). The separate reductions in macrovascular and microvascular events were similar but were not independently significant (macrovascular 0.92; 0.81-1.04, p=0.16; microvascular 0.91; 0.80-1.04, p=0.16). The relative risk of death from cardiovascular disease was reduced by 18% (211 [3.8%] active vs 257 [4.6%] placebo; 0.82, 0.68-0.98, p=0.03) and death from any cause was reduced by 14% (408 [7.3%] active vs 471 [8.5%] placebo; 0.86, 0.75-0.98, p=0.03). There was no evidence that the effects of the study treatment differed by initial blood pressure level or concomitant use of other treatments at baseline. INTERPRETATION: Routine administration of a fixed combination of perindopril and indapamide to patients with type 2 diabetes was well tolerated and reduced the risks of major vascular events, including death. Although the confidence limits were wide, the results suggest that over 5 years, one death due to any cause would be averted among every 79 patients assigned active therapy.

The impact of level of education on vascular events and mortality in patients with type 2 diabetes mellitus: Results from the ADVANCE study.

AIMS: The relationship between educational level and the risk of all-cause mortality is well established, whereas the association with vascular events in individuals with type 2 diabetes is not well described. Any association may reflect a link with common cardiovascular or lifestyle-based risk factors. METHODS: The relationships between the highest level of educational attainment and major cardiovascular events, microvascular complications and all-cause mortality were explored in a cohort of 11,140 individuals with type 2 diabetes. Completion of formal education before the age of 16 was categorized as a low level of education. Regional differences between Asia, East Europe and Established Market Economies were also assessed. RESULTS: During a median of 5years of follow up, 1031 (9%) patients died, 1147 (10%) experienced a major cardiovascular event and 1136 (10%) a microvascular event. After adjustment for baseline characteristics and risk factors, individuals with lower education had an increased risk of cardiovascular events (hazard ratio (HR) 1.31, 95% CI 1.16-1.48, p<0.0001), microvascular events (HR 1.23, 95% CI 1.08-1.39, p=0.0013) and all-cause mortality (HR 1.34, 95% CI 1.18-1.52, p<0.0001). In regional analyses the increased risk of studied outcomes associated with lower education was weakest in Established Market Economies and strongest in East Europe. CONCLUSIONS: A low level of education is associated with an increased risk of vascular events and death in patients with type 2 diabetes, independently of common lifestyle associated cardiovascular risk factors. The effect size varies between geographical regions.

Clustering of glycoprotein VI (GPVI) dimers upon adhesion to collagen as a mechanism to regulate GPVI signaling in platelets.

Essentials Dimeric high-affinity collagen receptor glycoprotein VI (GPVI) is present on resting platelets. Spatio-temporal organization of platelet GPVI-dimers was evaluated using advanced microscopy. Upon platelet adhesion to collagenous substrates, GPVI-dimers coalesce to form clusters. Clustering of GPVI-dimers may increase avidity and facilitate platelet activation SUMMARY: Background Platelet glycoprotein VI (GPVI) binding to subendothelial collagen exposed upon blood vessel injury initiates thrombus formation. Dimeric GPVI has high affinity for collagen, and occurs constitutively on resting platelets. Objective To identify higher-order oligomerization (clustering) of pre-existing GPVI dimers upon interaction with collagen as a mechanism to initiate GPVI-mediated signaling. Methods GPVI was located by use of fluorophore-conjugated GPVI dimer-specific Fab (antigen-binding fragment). The tested substrates include Horm collagen I fibers, soluble collagen III, GPVI-specific collagen peptides, and fibrinogen. GPVI dimer clusters on the platelet surface interacting with these substrates were visualized with complementary imaging techniques: total internal reflection fluorescence microscopy to monitor real-time interactions, and direct stochastic optical reconstruction microscopy (dSTORM), providing relative quantification of GPVI cluster size and density. Confocal microscopy was used to locate GPVI dimer clusters, glycoprotein Ib, integrin α2 ß1 , and phosphotyrosine. Results Upon platelet adhesion to all collagenous substrates, GPVI dimers coalesced to form clusters; notably clusters formed along the fibers of Horm collagen. dSTORM revealed that GPVI density within clusters depended on the substrate, collagen III being the most effective. Clusters on fibrinogen-adhered platelets were much smaller and more numerous; whether these are pre-existing oligomers of GPVI dimers or fibrinogen-induced is not clear. Some GPVI dimer clusters colocalized with areas of phosphotyrosine, indicative of signaling activity. Integrin α2 ß1 was localized to collagen fibers close to GPVI dimer clusters. GPVI clustering depends on a dynamic actin cytoskeleton. Conclusions Platelet adhesion to collagen induces GPVI dimer clustering. GPVI clustering increases both avidity for collagen and the proximity of GPVI-associated signaling molecules, which may be crucial for the initiation and persistence of signaling.

ADVANCE: action in diabetes and vascular disease.

The burden of Type II diabetes is growing rapidly worldwide, across high-, middle- and low-income countries. This burden is associated primarily with increased risks of macrovascular and microvascular diseases, and it is agreed that multifactorial treatment regimens are required to reduce it. ADVANCE (Action in Diabetes and Vascular disease: Preterax and Diamicron-MR Controlled Evaluation) is a large-scale, 2 x 2 factorial, randomised clinical trial. It will investigate the potential benefits of blood pressure lowering, using a fixed low-dose combination of perindopril and indapamide vs placebo, and of tighter glucose control, using an intensive gliclazide-MR-based glucose control regimen vs a standard guidelines-based regimen, separately and together. The two primary outcomes are a composite macrovascular end point of nonfatal stroke, nonfatal myocardial infarction and cardiovascular death; and a composite microvascular end point of new or worsening nephropathy or microvascular eye disease. Following successful recruitment and randomisation of 11,140 participants by March 2003, the study is currently half way through its planned follow-up of 4.5 years. Adherence to randomised study treatment is good; and loss to follow-up is minimal. It is hoped that the study will answer a number of unresolved issues. The blood pressure lowering arm will investigate the possible reduction in major vascular disease in patients with Type II diabetes whether or not they have hypertension, and the possible benefits of blood pressure lowering in such patients already receiving background therapy with the ACE inhibitor perindopril. The glucose control arm will investigate the possible reduction in both macrovascular and microvascular disease achieved with tighter glucose control, targeting an HbA1c of 6.5% and a fasting blood glucose of 6.0 mmol/l. Finally, the factorial design will enable investigation of the combined effects of more intensive glucose control and tighter control of blood pressure.

The effects of antihypertensive therapy on carotid vascular structure in man.

OBJECTIVE: An increased carotid intima-media thickness (IMT) has been found to be associated with a number of cardiovascular risk factors such as age, hypertension, cigarette smoking, hypercholesterolaemia and left ventricular hypertrophy. Our objective was to assess whether carotid intima-media thickness in hypertensive patients could be reduced by antihypertensive therapy. METHODS: 13 hypertensive patients, 10 previously untreated, were examined using carotid ultrasonography and echocardiography at baseline and then at 8 weeks and 39 weeks after commencement of antihypertensive therapy with ramipril and the second-line addition of felodipine. RESULTS: By the end of the study significant regression of IMT (0.1(0.05-0.16) mm, F-value 10.2, P < 0.01) and left ventricular mass index had occurred (25(10.7-39.3) g/m2, F-value 9.7, P < 0.01). The reduction in IMT was significantly related to the reduction in mean arterial pressure, r = 0.55, P = 0.05). CONCLUSION: Antihypertensive therapy with ramipril and felodipine causes regression of IMT in hypertensive patients, probably chiefly through blood pressure reduction. Large prospective studies are required to assess whether a reduction in IMT results in a reduction in morbidity and mortality.

Development of the roadmap and guidelines for the prevention and management of high blood pressure in Africa: Proceedings of the PASCAR Hypertension Task Force meeting: Nairobi, Kenya, 27 October 2014.

Africa has one of the fastest growing economies in the world. The economic changes are associated with a health transition characterised by a rise in cardiovascular risk factors and complications, which tend to affect the African population at their age of maximum productivity. Recent data from Africa have highlighted the increasing importance of high blood pressure in this region of the world. This condition is largely underdiagnosed and poorly treated, and therefore leads to stroke, renal and heart failure, and death. Henceforth, African countries are taking steps to develop relevant policies and programmes to address the issue of blood pressure and other cardiovascular risk factors in response to a call by the World Health Organisation (WHO) to reduce premature deaths from non-communicable diseases (NCDs) by 25% by the year 2025 (25 × 25). The World Heart Federation (WHF) has developed a roadmap for global implementation of the prevention and management of raised blood pressure using a health system approach to help realise the 25 × 25 goal set by the WHO. As the leading continental organisation of cardiovascular professionals, the Pan-African Society of Cardiology (PASCAR) aims to contextualise the roadmap framework of the WHF to the African continent through the PASCAR Taskforce on Hypertension. The Taskforce held a workshop in Kenya on 27 October 2014 to discuss a process by which effective prevention and control of hypertension in Africa may be achieved. It was agreed that a set of clinical guidelines for the management of hypertension are needed in Africa. The ultimate goal of this work is to develop a roadmap for implementation of the prevention and management of hypertension in Africa under the auspices of the WHF.

Left ventricular hypertrophy and QT dispersion in hypertension.

The interlead variation in QT length on a standard electrocardiograph reflects regional repolarization differences in the heart. To investigate the association between this interlead variation (QT dispersion) and left ventricular hypertrophy, we subjected 100 untreated subjects to 12-lead electrocardiography and echocardiography. Additionally, 24 previously untreated subjects underwent a 6-month treatment study with ramipril and felodipine. In the cross-sectional part of the study, QT dispersion corrected for heart rate (QTc dispersion) was significantly correlated with left ventricular mass index (r = .30, P < .01), systolic pressure (r = .30, P < .01), the ratio of peak flow velocity of the early filling wave to peak flow velocity of the atrial wave (E/A ratio) (r = -.22, P = .02), isovolumic relaxation time (r = .31, P < .01), and age (r = .21, P < .04). In the treatment part of the study, lead-adjusted QTc dispersion decreased from 24 to 19 milliseconds after treatment, and after a subsequent 2 weeks of drug washout remained at 19 milliseconds (P < .01). The changes in left ventricular mass index at these stages were 144, 121, and 124 g/m2 (P < .01). Systolic pressure decreased from 175 to 144 mm Hg and increased again to 164 mm Hg after drug washout (P < .01). The E/A ratio (0.97, 1.02, and 1.02; P = 69) and isovolumic relaxation time (111, 112, and 112; P = .97) remained unchanged through the three assessment points. In conclusion, QT dispersion is increased in association with an increased left ventricular mass index in hypertensive individuals. Antihypertensive therapy with ramipril and felodipine reduced both parameters. If an increased QT dispersion is a predictor of sudden death in this group of individuals, then the importance of its reduction is evident.