William David Strain

Ethnic differences in vascular stiffness and relations to hypertensive target organ damage.

Objective People of Black African descent have greater risks of hypertensive target organ damage than would be anticipated for given levels of blood pressure. Arterial stiffness may further account for ethnic differences in risk. Design Cross-sectional study. Setting Population based, London, UK. Participants One hundred and three Europeans and 99 African Caribbeans aged 40–64 years. Methods We measured resting and ambulatory blood pressure, and pulse wave velocity (PWV) of elastic and muscular arteries. Echocardiography measured interventricular septal thickness (IVST). Main outcome measures PWV, IVST. Results Carotid–femoral PWV was 12.7 m/s [95% confidence interval (CI) 12.3, 13.1] in African Caribbeans and 11.2 m/s (10.9, 11.6) in Europeans (P < 0.0001). This difference persisted on adjustment for resting and ambulatory blood pressure, 12.4 versus 11.5 m/s (P = 0.003). The greater IVST in African Caribbeans (9.6 mm) compared to Europeans (9.1 mm, P = 0.0005), could only in part be accounted for by differences in carotid–femoral PWV. Stiffness in the muscular carotid–radial segment did not differ by ethnicity, but was positively associated with systolic pressure in Europeans (β regression coefficient 0.033, P = 0.04), and negatively associated in African Caribbeans (−0.036, P = 0.04, and P = 0.02 for interaction). Conclusions Aortic stiffness is increased in African Caribbeans compared to Europeans, even when higher blood pressures are accounted for. It is most closely related to IVST, but contributes little to explaining ethnic differences. Stiffness of the upper limb muscular arteries did not differ by ethnicity, but remained favourable in the presence of hypertension in African Caribbeans, while being increased in Europeans. We suggest that this is due to ethnic differences in vascular remodelling.

Ethnic differences in skin microvascular function and their relation to cardiac target-organ damage.

Background People of Black African descent have increased risks of vascular target-organ damage not explained by greater blood pressures. Objective To study ethnic differences in the microvasculature. Design and methods Flow (flux) in microcirculatory skin vessels was assessed using laser Doppler fluximetry in 181 Afro-Caribbean and European men and women aged 40–65 years from the general population in London, UK. Flux in response to maximal heating (maximal hyperaemic response) was measured and minimum vascular resistance calculated. Peak flux and time to peak after an ischaemic stimulus were also measured. Target-organ damage was assessed using echocardiographic interventricular septal thickness (IVST). Results In men, maximum hyperaemic response was attenuated in Afro-Caribbeans [109 arbitrary units (au), 25th and 75th percentiles 101, 117] compared with Europeans [165 (155, 179) au; P = 0.008]. Minimum vascular resistance was greater in Afro-Caribbeans, significantly so in men [(1.22 (1.18, 1.28) au/mmHg compared with 0.80 (0.77, 0.83) au/mmHg; P = 0.006]. Peak ischaemic response was attenuated in Afro-Caribbean men and women compared with Europeans (35.6 au compared with 49.5 au; P < 0.001) and time to peak was prolonged (14.1 s compared with 12.5 s; P = 0.07). These ethnic differences could not be accounted for by standard cardiovascular risk factors. IVST was greater in Afro-Caribbeans than in Europeans. Minimum vascular resistance and peak response accounted for a small proportion of this ethnic difference, in addition to conventional factors. Conclusions Afro-Caribbeans have poorer microvascular structure and function, unexplained by conventional risk factors, which may contribute to greater rates of vascular target-organ damage.

Clinical Inertia in Individualising Care for Diabetes: Is There Time to do More in Type 2 Diabetes?

Clinical inertia is defined as the failure to establish appropriate targets and escalate treatment to achieve treatment goals. It accounts for a significant proportion of failure to achieve targets in the management of diabetes and contributes to up to 200,000 adverse diabetes- related outcomes per year. Despite a growing awareness of the phenomenon, and newer, better-tolerated agents for the control of diabetes, there has been little improvement over the last decade in the prevalence of clinical inertia. Although common-place in clinical practice, clinical inertia does not appear to affect clinical trials. There are lessons that may be translated from these randomised controlled trials to clinical practice, which that may improve the care for those with diabetes. Key amongst these interventions are good education, clear treatment strategy and more time for interaction between physician and patients, all of which appears to reduce clinical inertia as evidenced by the “placebo effect” of clinical trials. We plan to review here, the lessons that can be learnt from clinical trials and how these may translate to better care for people with diabetes.

Associations between cardiac target organ damage and microvascular dysfunction: the role of blood pressure

Background Microvascular dysfunction may be an early precursor of cardiovascular disease (CVD). Increased left ventricular mass (LVM), concentric left ventricular remodelling and increased left atrial size are the factors that could predict future CVD. We investigated whether microvascular dysfunction was associated with these cardiac measures. Methods and results Laser Doppler fluximetry of skin vessels was used to study associations with risk factors and echocardiographic measurements of LVM, relative wall thickness (RWT), and left atrial size in 305 people (aged 40–65 years; 117 with type 2 diabetes). Flow in response to a 3-min arterial occlusion was measured. Postischaemic peak flow responses were categorized into three distinct groups: slow rise to peak (normal), nondominant early peak group (mildly abnormal) and a dominant early peak (abnormal). Those with a dominant early peak had higher blood pressure (P = 0.001), weight (P = 0.001), fasting glucose (P = 0.001) and prevalence of diabetes (P = 0.02). LVM (P = 0.01), RWT (P < 0.001) and left atrial size (P < 0.001) were greater with worsening postischaemic peak flow responses. Differences in LVM between postischaemic response groups were accounted for by blood pressure (BP). However, differences in BP and other CVD risk factors did not account for the greater RWT and left atrial size observed in the more adverse peak response groups [geometric mean of RWT [95% confidence interval (CI)] 0.40 (0.38–0.41) vs. 0.41 (0.40–0.42) vs. 0.43 (0.41–0.45), P = 0.007; left atrial size 36.1 (35.4–36.1) vs. 37.4 (36.8–38.0) vs. 38.7 (37.5–40.0), P = 0.002 for normal vs. mildly abnormal vs. abnormal respectively]. Conclusion An abnormal microcirculatory cutaneous peak flow response following ischaemia is associated with adverse cardiac remodelling, independent of CVD risk factors including blood pressure.

Differences in the association between type 2 diabetes and impaired microvascular function among Europeans and African Caribbeans.

Aims/hypothesisDiabetes is associated with microvascular damage in all populations, but diabetic patients of Black African descent (African Caribbeans) have a greater risk of vascular target organ damage than would be anticipated for any given blood pressure level. We investigated whether this may be due to differences in the microvasculature.Materials and methodsTo assess the maximum hyperaemic response to heating and the post-ischaemic response, Laser Doppler fluximetry was performed on 51 and 100 Europeans, and on 66 and 88 African Caribbeans with and without diabetes, respectively. Subjects were aged between 40 and 65 years and recruited from the general population. Echocardiographic interventricular septal thickness (IVST) was measured as a proxy for vascular target organ damage.ResultsIn diabetic subjects of both ethnic groups, the maximum hyperaemic response and peak response to ischaemia were attenuated as compared to the corresponding non-diabetic subjects (p=0.08 for diabetic and 0.03 for non-diabetic Europeans; p=0.03 and 0.1 for African Caribbeans). Adjustment for cardiovascular risk factors, in particular insulin and blood pressure, abolished these differences in Europeans (p=0.8 for diabetic and 0.2 for non-diabetic Europeans), but not in African Caribbeans (p=0.03 and 0.05).Conclusions/interpretationPersisting microvascular dysfunction in African Caribbeans may contribute to the increased risk of target organ damage observed in diabetes in this population. The weak contribution of conventional cardiovascular risk factors to these disturbances indicates that conventional therapeutic interventions may be less beneficial in these patients. There was a risk-factor-independent, inverse association between IVST and maximal hyperaemia. These ethnic differences in microvascular responses to temperature and arterial occlusion could account for increased target organ damage in African Caribbeans.

Attenuation of microvascular function in those with cardiovascular disease is similar in patients of Indian Asian and European descent

BackgroundIndian Asians are at increased risk of cardiovascular death which does not appear to be explained by conventional risk factors. As microvascular disease is also more prevalent in Indian Asians, and as it is thought to play a role in the development of macrovascular disease, we decided to determine whether impaired microcirculation could contribute to this increased cardiovascular risk in Indian Asians.MethodsForearm skin laser Doppler fluximetry in response to heating and ischaemia was assessed in 83 Europeans (41 with angiographically confirmed atherosclerotic coronary artery disease (CAD) and 42 from the general population) and 84 Indian Asians (41 with CAD). Explanations for differences in microvascular function were sought using multivariate analysis including conventional cardiovascular risk factors.ResultsCompared to ethnically matched control populations both Europeans and Indian Asians with CAD had poorer microvascular responses to heating than those without (117(95% CI 105-131) vs. 142(130-162) arbitrary units, (au) for Europeans and 111(101-122) vs. 141(131-153)au for Indian Asians) and to ischaemia (44(38-50) vs. 57(49-67)au & 39(34-45) vs. 49(43-56)au respectively). These differences were not accounted for by conventional cardiovascular risk factors. There was no ethnic difference in the attenuation of microvascular function associated with CAD.ConclusionPatients of European and Indian Asian descent with symptomatic CAD have poorer microvascular maximal tissue perfusion and reactive hyperaemia in the skin compared to ethnically matched asymptomatic control populations. Despite the increased cardiovascular risk in Indian Asians, the attenuation of microvascular function associated with CAD was equivalent in the ethic groups. This suggests that in Indian Asians microcirculation does not explain the increased susceptibility to CAD.

Impaired post-ischaemic microvascular hyperaemia in Indian Asians is unexplained by diabetes or other cardiovascular risk factors

OBJECTIVE People of Indian Asian descent have an increased risk of cardiovascular disease (CVD) that cannot be explained by diabetes and other established CVD risk factors. We investigated if microcirculatory function was impaired in a population-based sample of people of Indian Asian descent compared with Europeans in the UK and whether any differences could be accounted for by diabetes or other CVD risk factors. RESEARCH DESIGN AND METHODS Cutaneous microvascular function was assessed using laser Doppler fluximetry in response to heating to 42 °C (maximum hyperaemia) and 3 min arterial occlusion (post occlusive reactive hyperaemia: PORH) in 148 Indian Asians and 147 Europeans. Blood pressure, anthropometry and fasting bloods were also measured. RESULTS Maximum hyperaemia and minimum resistance did not differ significantly by ethnicity. Resting flux and PORH were lower in Indian Asians and time to peak of PORH was prolonged. Diabetes was associated with reduced maximum hyperaemia and PORH. Adjustment for diabetes accounted for differences in resting flux and time to peak but not differences in PORH (Europeans = 45.0 (40.3, 50.1)au, Indian Asians = 35.6 (31.9, 39.7)au, mean (95% confidence interval); p = 0.008 after adjustment). Differences in conventional CVD risk factors did not account for interethnic differences in microvascular responses. CONCLUSIONS People of Indian Asian descent have impaired post-occlusive reactive hyperaemia unexplained by diabetes, dysglycaemia or other CVD risk factors. Abnormal microvascular function in response to ischaemia could represent a novel mechanism contributing to the elevated risk of CVD in Indian Asians.

Dipeptidyl Peptidase-4 Inhibitor Development and Post-authorisation Programme for Vildagliptin - Clinical Evidence for Optimised Management of ChronicDiseases Beyond Type 2 Diabetes

Abstract The last decade has witnessed the role of dipeptidyl peptidase-4 (DPP-4) inhibitors in producing a conceptual change in early management of type 2 diabetes mellitus (T2DM) by shifting emphasis from a gluco-centric approach to holistically treating underlying pathophysiological processes. DPP-4 inhibitors highlighted the importance of acknowledging hypoglycaemia and weight gain as barriers to optimised care in T2DM. These complications were an integral part of diabetes management before the introduction of DPP-4 inhibitors. During the development of DPP-4 inhibitors, regulatory requirements for introducing new agents underwent substantial changes, with increased emphasis on safety. This led to the systematic collection of adjudicated cardiovascular (CV) safety data, and, where 95% confidence of a lack of harm could not be demonstrated, the standardised CV safety studies. Furthermore, the growing awareness of the worldwide extent of T2DM demanded a more diverse approach to recruitment and participation in clinical trials. Finally, the global financial crisis placed a new awareness on the health economics of diabetes, which rapidly became the most expensive disease in the world. This review encompasses unique developments in the global landscape, and the role DPP-4 inhibitors, specifically vildagliptin, have played in research advancement and optimisation of diabetes care in a diverse population with T2DM worldwide.

Measurement of Wall Shear Stress Exerted by Flowing Blood in the Human Carotid Artery: Ultrasound Doppler Velocimetry and Echo Particle Image Velocimetry

Vascular endothelial cells lining the arteries are sensitive to wall shear stress (WSS) exerted by flowing blood. An important component of the pathophysiology of vascular diseases, WSS is commonly estimated by centerline ultrasound Doppler velocimetry (UDV). However, the accuracy of this method is uncertain. We have previously validated the use of a novel, ultrasound-based, particle image velocimetry technique (echo PIV) to compute 2-D velocity vector fields, which can easily be converted into WSS data. We compared WSS data derived from UDV and echo PIV in the common carotid artery of 27 healthy participants. Compared with echo PIV, time-averaged WSS was lower using UDV (28 ± 35%). Echo PIV revealed that this was due to considerable spatiotemporal variation in the flow velocity profile, contrary to the assumption that flow is steady and the velocity profile is parabolic throughout the cardiac cycle. The largest WSS underestimation by UDV was found during peak systole (118 ± 16%) and the smallest during mid-diastole (4.3± 46%). The UDV method underestimated WSS for the accelerating and decelerating systolic measurements (68 ± 30% and 24 ± 51%), whereas WSS was overestimated for end-diastolic measurements (-44 ± 55%). Our data indicate that UDV estimates of WSS provided limited and largely inaccurate information about WSS and that the complex spatiotemporal flow patterns do not fit well with traditional assumptions about blood flow in arteries. Echo PIV-derived WSS provides detailed information about this important but poorly understood stimulus that influences vascular endothelial pathophysiology.

Use of near-infrared systems for investigations of hemodynamics in human in vivo bone tissue: A systematic review: NIR FOR HEMODYNAMIC BONE MEASUREMENTS

A range of technologies using near infrared (NIR) light have shown promise at providing real time measurements of hemodynamic markers in bone tissue in vivo, an exciting prospect given existing difficulties in measuring hemodynamics in bone tissue. This systematic review aimed to evaluate the evidence for this potential use of NIR systems, establishing their potential as a research tool in this field. Major electronic databases including MEDLINE and EMBASE were searched using pre‐planned search strategies with broad scope for any in vivo use of NIR technologies in human bone tissue. Following identification of studies by title and abstract screening, full text inclusion was determined by double blind assessment using predefined criteria. Full text studies for inclusion were data extracted using a predesigned proforma and quality assessed. Narrative synthesis was appropriate given the wide heterogeneity of included studies. Eighty‐eight full text studies fulfilled the inclusion criteria, 57 addressing laser Doppler flowmetry (56 intra‐operatively), 21 near infrared spectroscopy, and 10 photoplethysmography. The heterogeneity of the methodologies included differing hemodynamic markers, measurement protocols, anatomical locations, and research applications, making meaningful direct comparisons impossible. Further, studies were often limited by small sample sizes with potential selection biases, detection biases, and wide variability in results between participants. Despite promising potential in the use of NIR light to interrogate bone circulation, the application of NIR systems in bone requires rigorous assessment of the reproducibility of potential hemodynamic markers and further validation of these markers against alternative physiologically relevant reference standards.