Alun D. Hughes

Development and validation of a new adenosine-independent index of stenosis severity from coronary wave-intensity analysis: results of the ADVISE (ADenosine Vasodilator Independent Stenosis Evaluation) study.

OBJECTIVES The purpose of this study was to develop an adenosine-independent, pressure-derived index of coronary stenosis severity. BACKGROUND Assessment of stenosis severity with fractional flow reserve (FFR) requires that coronary resistance is stable and minimized. This is usually achieved by administration of pharmacological agents such as adenosine. In this 2-part study, we determine whether there is a time when resistance is naturally minimized at rest and assess the diagnostic efficiency, compared with FFR, of a new pressure-derived adenosine-free index of stenosis severity over that time. METHODS A total of 157 stenoses were assessed. In part 1 (39 stenoses), intracoronary pressure and flow velocity were measured distal to the stenosis; in part 2 (118 stenoses), intracoronary pressure alone was measured. Measurements were made at baseline and under pharmacologic vasodilation with adenosine. RESULTS Wave-intensity analysis identified a wave-free period in which intracoronary resistance at rest is similar in variability and magnitude (coefficient of variation: 0.08 ± 0.06 and 284 ± 147 mm Hg s/m) to those during FFR (coefficient of variation: 0.08 ± 0.06 and 302 ± 315 mm Hg s/m; p = NS for both). The resting distal-to-proximal pressure ratio during this period, the instantaneous wave-free ratio (iFR), correlated closely with FFR (r = 0.9, p < 0.001) with excellent diagnostic efficiency (receiver-operating characteristic area under the curve of 93%, at FFR <0.8), specificity, sensitivity, negative and positive predictive values of 91%, 85%, 85%, and 91%, respectively. CONCLUSIONS Intracoronary resistance is naturally constant and minimized during the wave-free period. The instantaneous wave-free ratio calculated over this period produces a drug-free index of stenosis severity comparable to FFR. (Vasodilator Free Measure of Fractional Flow Reserve [ADVISE]; NCT01118481).

Evidence of a Dominant Backward-Propagating “Suction” Wave Responsible for Diastolic Coronary Filling in Humans, Attenuated in Left Ventricular Hypertrophy

Background— Coronary blood flow peaks in diastole when aortic blood pressure has fallen. Current models fail to completely explain this phenomenon. We present a new approach—using wave intensity analysis—to explain this phenomenon in normal subjects and to evaluate the effects of left ventricular hypertrophy (LVH). Method and Results— We measured simultaneous pressure and Doppler velocity with intracoronary wires in the left main stem, left anterior descending, and circumflex arteries of 20 subjects after a normal coronary arteriogram. Wave intensity analysis was used to identify and quantify individual pressure and velocity waves within the coronary artery circulation. A consistent pattern of 6 predominating waves was identified. Ninety-four percent of wave energy, accelerating blood forward along the coronary artery, came from 2 waves: first a pushing wave caused by left ventricular ejection—the dominant forward-traveling pushing wave; and later a suction wave caused by relief of myocardial microcirculatory compression—the dominant backward-traveling suction wave. The dominant backward-traveling suction wave (18.2±13.7×103 W m−2 s−1, 30%) was larger than the dominant forward-traveling pushing wave (14.3±17.6×103 W m−2 s−1, 22.3%, P =0.001) and was associated with a substantially larger increment in coronary blood flow velocity (0.51 versus 0.14 m/s, P<0.001). In LVH, the dominant backward-traveling suction wave percentage was significantly decreased (33.1% versus 26.9%, P=0.01) and inversely correlated with left ventricular septal wall thickness (r=−0.52, P<0.02). Conclusions— Six waves predominantly drive human coronary blood flow. Coronary flow peaks in diastole because of the dominance of a “suction” wave generated by myocardial microcirculatory decompression. This is significantly reduced in LVH.

Blood flow and vessel mechanics in a physiologically realistic model of a human carotid arterial bifurcation

The pulsatile flow in an anatomically realistic compliant human carotid bifurcation was simulated numerically. Pressure and mass flow waveforms in the carotid arteries were obtained from an individual subject using non-invasive techniques. The geometry of the computational model was reconstructed from magnetic resonance angiograms. Maps of time-average wall shear stress, contours of velocity in the flow field as well as wall movement and tensile stress on the arterial wall are all presented. Inconsistent with previous findings from idealised geometry models, flow in the carotid sinus is dominated by a strong helical flow accompanied by a single secondary vortex motion. This type of flow is induced primarily by the asymmetry and curvature of the in vivo geometry. Flow simulations have been carried out under the rigid wall assumption and for the compliant wall, respectively. Comparison of the results demonstrates the quantitative influence of the vessel wall motion. Generally there is a reduction in the magnitude of wall shear stress, with its degree depending on location and phase of the cardiac cycle. The region of slow or reversed flow was greater, in both spatial and temporal terms in the compliant model, but the global characteristics of the flow and stress patterns remain unchanged. The analysis of mechanical stresses on the vessel surface shows a complicated stress field. Stress concentration occurs at both the anterior and posterior aspects of the proximal internal bulb. These are also regions of low wall shear stress. The comparison of computed and measured wall movement generally shows good agreement.

Abnormalities of Retinal Microvascular Structure and Risk of Mortality From Ischemic Heart Disease and Stroke

Abnormalities of the retinal microcirculation are found in hypertension and diabetes and predict cardiovascular mortality. This study examined the relationship between abnormalities of the retinal microvasculature and death from ischemic heart disease (IHD) and stroke. A population-based, nested case-control study was undertaken within the Beaver Dam Eye Study. Subjects (43 to 74 years) who died of IHD (n=126) or stroke (n=28) over a 10-year period were age and gender matched with controls subjects (n=528; case:control matching, ≈1:4). Retinal photographs of cases and controls were digitized and analyzed using a computer-based technique. Increased risk of IHD death was associated with a suboptimal relationship of arteriolar diameters at bifurcation (P=0.02 unadjusted) and decreased retinal arteriolar tortuosity (P=0.011 unadjusted). These associations remained significant after adjustment for age, sex, past history of cardiovascular disease, and other known cardiovascular risk factors. Increased arteriolar length:diameter ratio, a measure of generalized arteriolar narrowing, was associated with increased stroke mortality (P=0.02 unadjusted). This association was independent of age and gender but was attenuated by adjustment for systolic blood pressure (P=0.15). Other quantitative measures of the retinal microvascular network (eg, venular tortuosity and arteriolar and venular bifurcation angle) were not associated with death from IHD or stroke. Retinal microvascular abnormalities are predictive of death from IHD and stroke. A detailed assessment of the retinal microvascular network from digitized photographs may be useful in the noninvasive assessment of target organ damage and cardiovascular risk.

Endothelial von Willebrand factor regulates angiogenesis

The regulation of blood vessel formation is of fundamental importance to many physiological processes, and angiogenesis is a major area for novel therapeutic approaches to diseases from ischemia to cancer. A poorly understood clinical manifestation of pathological angiogenesis is angiodysplasia, vascular malformations that cause severe gastrointestinal bleeding. Angiodysplasia can be associated with von Willebrand disease (VWD), the most common bleeding disorder in man. VWD is caused by a defect or deficiency in von Willebrand factor (VWF), a glycoprotein essential for normal hemostasis that is involved in inflammation. We hypothesized that VWF regulates angiogenesis. Inhibition of VWF expression by short interfering RNA (siRNA) in endothelial cells (ECs) caused increased in vitro angiogenesis and increased vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2)-dependent proliferation and migration, coupled to decreased integrin αvβ3 levels and increased angiopoietin (Ang)-2 release. ECs expanded from blood-derived endothelial progenitor cells of VWD patients confirmed these results. Finally, 2 different approaches, in situ and in vivo, showed increased vascularization in VWF-deficient mice. We therefore identify a new function of VWF in ECs, which confirms VWF as a protein with multiple vascular roles and defines a novel link between hemostasis and angiogenesis. These results may have important consequences for the management of VWD, with potential therapeutic implications for vascular diseases.

First-in-man safety evaluation of renal denervation for chronic systolic heart failure: primary outcome from REACH-Pilot study.

BACKGROUND Sympathetic overactivation, is reduced by renal denervation in drug-resistant hypertension. A similar role for renal denervation in heart failure remains unstudied, partly due to the concern about potential concomitant deleterious blood pressure reductions. This pilot study evaluated the safety of renal denervation for heart failure using an intensive follow-up protocol. METHOD 7 patients (mean age 69 years) with chronic systolic heart failure (mean BP on referral 112/65 mmHg) on maximal tolerated heart failure therapy underwent bilateral renal denervation May-July 2011. Patients were admitted for pre-procedure baseline assessments and in-patient observation for 5 days following denervation. Follow-up was weekly for 4 weeks, and then monthly for 6 months. RESULTS No significant haemodynamic disturbances were noted during the acute phase post renal denervation. Over 6 months there was a non-significant trend to blood pressure reduction (Δsystolic -7.1 ± 6.9 mmHg, p=0.35; Δdiastolic -0.6 ± 4.0 mmHg, p=0.88). No hypotensive or syncopal episodes were reported. Renal function remained stable (Δcreatinine -5.7 ± 8.4 μmol/l, p=0.52 and Δurea -1.0 ± 1.0 mmol/l, p=0.33). All 7 patients described themselves as symptomatically improved. The six minute walk distance at six months was significantly increased (Δ=27.1 ± 9.7 m, p=0.03), with each patient showing an increase. CONCLUSIONS This study found no procedural or post procedural complications following renal denervation in patients with chronic systolic heart failure in 6 months of intensive follow-up. Results suggested improvements in both symptoms and exercise capacity, but further randomised, blinded sham-controlled clinical trials are required to determine the impact of renal denervation on morbidity and mortality in systolic heart failure. These data suggest such trials will be safe. ClinicalTrial.gov NCT01584700

Cohort Profile: Updating the cohort profile for the MRC National Survey of Health and Development: a new clinic-based data collection for ageing research

MRC Unit for Lifelong Health and Ageing, Research Department of Epidemiology and Public Health, University College London, London, UK, Clinical Radiology, Manchester Royal Infirmary, Oxford Road, Manchester, UK, Vascular Physiology Unit, Institute of Child Health, University College London, London, UK, MRC Epidemiology Unit, Cambridge, UK, Cardiovacular Institute, Sahlgrenska University Hospital, Göteborg, Sweden, Wellcome Trust Clinical Research Facility Manchester, Manchester, UK, International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, London, UK, Institute of Cardiovascular & Medical Sciences, University of Glasgow, Glasgow, UK, Department of Echocardiography, The Heart Hospital, London, UK and MRC Human Nutrition Research, Cambridge, UK

Vascular network changes in the retina with age and hypertension

Objective To compare retinal arterial bifurcation geometry in normotensive and hypertensive subjects. Design A retrospective observational study. Methods Fluorescein angiograms of normotensive (n = 13) and hypertensive (n = 12) subjects aged 30–80 years with uni-ocular retinal pathology were compared. Quantification of diameters of the parent, larger daughter and smaller daughter vessels (d0, d1 and d2, respectively) and of bifurcation angles (the angle between the two daughter arterioles, oM) of arteriolar bifurcations was performed from digitized retinal angiograms of the uninvolved eye. The relative diameters of parent and daughter vessels at bifurcations were summarized by junction exponents (x) such that d1x + d2x = d0x. Results Junction exponents were similar for normotensives and hypertensives (means ± SEM, 2.65 ± 0.18 and 2.48 ± 0.17), but analysis of covariance showed a parallel decrease in x in the two groups with age. A positive association was found between x and arteriolar microvascular density. Bifurcation angles were more acute in hypertensives (74 ± 3±) than in normotensives (84 ± 3±) and declined with increasing age in both groups. Conclusions The present findings indicate that ageing and possibly hypertension are associated with disadvantageous branching geometry in the human retinal vasculature, implying increased power costs of blood transport, uneven distribution of shear forces throughout the vascular tree and microvascular rarefaction. The present findings may have important implications for our understanding of the pathogenesis of vascular disease in ageing and hypertension and offer the prospect of a novel sensitive diagnostic approach to the cardiovascular system.

Retinal Blood Vessel Segmentation by Means of Scale-Space Analysis and Region Growing

We present a method for retinal blood vessel segmentation based upon the scale-space analysis of the first and second derivative of the intensity image which gives information about its topology and overcomes the problem of variations in contrast inherent in these images. We use the local maxima over scales of the magnitude of the gradient and the maximum principal curvature as the two features used in a region growing procedure. In the first stage, the growth is constrained to regions of low gradient magnitude. In the final stage this constraint is relaxed to allow borders between regions to be defined. The algorithm is tested in both red-free and fluorescein retinal images.

Tyrosine kinase inhibitors block calcium channel currents in vascular smooth muscle cells.

Selective inhibitors of tyrosine kinases, tyrphostin 23 and genistein, produced concentration-dependent inhibition of voltage-operated calcium channel currents in vascular smooth muscle cells isolated from rabbit ear artery. The potency of these two structurally dissimilar inhibitors was similar to that reported for their action as inhibitors of tyrosine kinases. Daidzein, an inactive analogue of genistein, had little inhibitory effect on calcium channel currents at concentrations below 300 microM consistent with an action of these agents at a tyrosine kinase. However, tyrphostin 1, a reportedly less active tyrphostin derivative, also inhibited calcium channel currents with a potency similar to tyrphostin 23. These findings suggest that voltage-operated calcium channels in vascular smooth muscle may be modulated by endogenous tyrosine kinase(s) which display different sensitivities to inhibitors compared with the epidermal growth factor (EGF) receptor. Alternatively the possibility of direct blocking actions of these inhibitors at voltage-operated calcium channels cannot be excluded.