S Thom

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.

Computer algorithms for the automated measurement of retinal arteriolar diameters.

AIMS Quantification of retinal vascular change is difficult and manual measurements of vascular features are slow and subject to observer bias. These problems may be overcome using computer algorithms. Three automated methods and a manual method for measurement of arteriolar diameters from digitised red-free retinal photographs were compared. METHODS 60 diameters (in pixels) measured by manual identification of vessel edges in red-free retinal images were compared with diameters measured by (1) fitting vessel intensity profiles to a double Gaussian function by non-linear regression, (2) a standard edge detection algorithm (Sobel), and (3) determination of points of maximum intensity variation by a sliding linear regression filter (SLRF). Method agreement was analysed using Bland–Altman plots and the repeatability of each method was assessed. RESULTS Diameter estimations obtained using the SLRF method were the least scattered although diameters obtained were approximately 3 pixels greater than those measured manually. The SLRF method was the most repeatable and the Gaussian method less so. The Sobel method was the least consistent owing to frequent misinterpretation of the light reflex as the vessel edge. CONCLUSION Of the three automated methods compared, the SLRF method was the most consistent (defined as the method producing diameter estimations with the least scatter) and the most repeatable in measurements of retinal arteriolar diameter. Application of automated methods of retinal vascular analysis may be useful in the assessment of cardiovascular and other diseases.

An international randomised placebo-controlled trial of a four-component combination pill ("polypill") in people with raised cardiovascular risk

Background There has been widespread interest in the potential of combination cardiovascular medications containing aspirin and agents to lower blood pressure and cholesterol (‘polypills’) to reduce cardiovascular disease. However, no reliable placebo-controlled data are available on both efficacy and tolerability. Methods We conducted a randomised, double-blind placebo-controlled trial of a polypill (containing aspirin 75 mg, lisinopril 10 mg, hydrochlorothiazide 12.5 mg and simvastatin 20 mg) in 378 individuals without an indication for any component of the polypill, but who had an estimated 5-year cardiovascular disease risk over 7.5%. The primary outcomes were systolic blood pressure (SBP), LDL-cholesterol and tolerability (proportion discontinued randomised therapy) at 12 weeks follow-up. Findings At baseline, mean BP was 134/81 mmHg and mean LDL-cholesterol was 3.7 mmol/L. Over 12 weeks, polypill treatment reduced SBP by 9.9 (95% CI: 7.7 to 12.1) mmHg and LDL-cholesterol by 0.8 (95% CI 0.6 to 0.9) mmol/L. The discontinuation rates in the polypill group compared to placebo were 23% vs 18% (RR 1.33, 95% CI 0.89 to 2.00, p = 0.2). There was an excess of side effects known to the component medicines (58% vs 42%, p = 0.001), which was mostly apparent within a few weeks, and usually did not warrant cessation of trial treatment. Conclusions This polypill achieved sizeable reductions in SBP and LDL-cholesterol but caused side effects in about 1 in 6 people. The halving in predicted cardiovascular risk is moderately lower than previous estimates and the side effect rate is moderately higher. Nonetheless, substantial net benefits would be expected among patients at high risk. Trial Registration Australian New Zealand Clinical Trials Registry ACTRN12607000099426

Human Vascular Responses to Endothelin-1: Observations in vivo and in vitro

Summary These studies have investigated the effect of endothelin-1 (ET-1) on human resistance vasculature in vivo and in vitro. ET-1 was infused via the brachial artery and forearm blood flow (FBF) measured by venous occlusion plethysmography. Isolated resistance vessels were studied in a myograph. ET-1 (10 pmol-10 nmol/min, i.a.) reduced forearm blood flow. Endothelin-1-induced forearm vasoconstriction was slow to recover following washout. ET-1 (10 pM-10 nM) contracted isolated human subcutaneous and omental resistance vessels. Contractile responses to ET-1 were sustained and washout recovery was slow. Responses to ET-1 displayed marked tachyphylaxis. Calcium channel blockers and removal of extracellular calcium failed to completely abolish responses to ET-1 in vitro.

Size and site-dependent heterogeneity of human vascular responses in vitro

Ring segments of splanchnic, peripheral, coronary, pulmonary and uterine conduit arteries obtained during surgery were studied in tissue baths. Resistance arteries dissected from various sites were studied in a myograph. Both conduit and resistance vessels contracted in response to the α1-agonist phenylephrine (10-7 to 10-4 mol/l), an effect that was antagonized by the α1-antagonist doxazosin (10-8 to 10-6 mol/l). However, the α2-agonists BHT 933 (10-7 to 10-4 mol/l) and UK 14304 (10-7 to 10-4 mol/l) only contracted the resistance vessels and not the conduit arteries. The response to BHT 933 was competitively antagonized by the α2-antagonist yohimbine (3.10-8 to 3.10-7 mol/l) and the magnitude of the contractile response was inversely related to vessel size. Similarly, neuropeptide Y (10-9 to 10-6 mol/l) contracted only the resistance vessels, and induced marked tachyphylaxis. Atrial natriuretic peptide (ANP; 10-8 to 10-6 mol/l) produced concentration-dependent relaxation in all conduit arteries studied, being ineffective in resistance arteries from subcutaneous or omental sites, but relaxed those from renal tissue and skeletal muscle. Calcitonin gene-related peptide (10-8 to 10-6 mol/l) and vasoactive intestinal peptide (10-9 to 10-6 mol/l) relaxed both conduit and resistance arteries. This response was dependent on the integrity of the endothelium in the systemic conduit but not the resistance vessels. These results indicate that the receptors for adrenergic agonists and vasoactive peptides are varyingly distributed throughout the human vasculature. The physiological relevance of these observations is not yet clear, but it is clearly important to the investigation of the sites of action of vasodilator drugs.

An intensive phenotyping study to enable the future examination of genetic influences on hypertension-associated cardiovascular disease.

A Stanton, D Fitzgerald, A Hughes, J Mayet, E O’Brien, NR Poulter, PS Sever, D Shields and S Thom Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, St Stephens Green, Dublin 2, Ireland; Department of Clinical Pharmacology and Therapeutics, Imperial College Medical School, St Mary’s Campus, Paddington, London W2 1PG, UK; Department of Cardiology, St Mary’s Hospital, Paddington, London W2 1PG, UK; Blood Pressure Unit, Beaumont Hospital, Dublin 9, Ireland

DOPAMINE PRODUCES FOREARM VASODILATATION FOLLOWING ALPHA-ADRENOCEPTOR BLOCKADE BY AN ACTION ON VASCULAR DOPAMINE (DA1) RECEPTORS IN MAN

The purpose of this study was to investigate the receptor type mediating dopamine-induced forearm vasodilatation following alpha-adrenoceptor blockade. Forearm blood flow (FBF) was measured using venous occlusion plethysmography in normal volunteers. Intra-arterial (i.a.) dopamine alone produced variable and small changes in FBF. However, following alpha-adrenoceptor blockade with phenoxybenzamine, dopamine infusion resulted in forearm vasodilatation in the infused arm. This effect was not antagonized by the beta-adrenoceptor antagonist propranolol, but was antagonized by the vascular dopamine receptor antagonist, sulpiride, the (d) enantiomer being more active than the (l). It is concluded that i.a. dopamine induces forearm vasodilatation following alpha-adrenoceptor blockade by an action on vascular dopamine (DA1) receptors similar to those described in the renal and mesenteric vasculature of other species.

Serum Amyloid A, C-Reactive Protein, and Retinal Microvascular Changes in Hypertensive Diabetic and Nondiabetic Individuals An Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) substudy

OBJECTIVE To study the association of the inflammatory markers serum amyloid A (SAA) and C-reactive protein (CRP) with retinal microvascular parameters in hypertensive individuals with and without type 2 diabetes. RESEARCH DESIGN AND METHODS This cross-sectional analysis was a substudy in 711 patients (159 with and 552 without diabetes) of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) based on digital 30-degree images of superior and inferior temporal retinal fields. RESULTS SAA was associated with arteriolar length-to-diameter ratio positively in nondiabetic patients (Ptrend= 0.028) but negatively in diabetic patients (Ptrend= 0.005). The difference was unlikely to be a chance finding (P = 0.007 for interaction). Similar results were found for the association of SAA with arteriolar tortuosity (P = 0.05 for interaction). Associations were less pronounced for CRP and retinal parameters. CONCLUSIONS Inflammatory processes are differentially involved in retinal microvascular disease in diabetic compared with nondiabetic hypertensive individuals.

Ethnic and gender differences in electrocardiographic QT length and QT dispersion in hypertensive subjects

Background: Prolonged QT intervals and/or increased QT dispersion (QTd) are associated with various pathological conditions and predict death in healthy individuals. Among hypertensives, QTd correlates with blood pressure (BP) and left ventricular mass index (LVMI) and QT intervals are prolonged in those with left ventricular hypertrophy (LVH). In normotensives, heart-rate corrected QT length (QTc) is longer in females than males, but QTd is greater in males than females. There are few data comparing QT parameters between different ethnic groups and none specifically in hypertensives. Among normotensives, compared with whites, QTc is reported to be shorter in African-Americans and longer in Chinese. We looked for ethnic and gender differences in QT parameters in hypertensive subjects.Methods: Untreated hypertensives were selected from a Hypertension Clinic database. Black and white subjects were matched for age, sex, BP and LVMI. Male and female subjects were matched for age, race, BP and the presence or absence of echocardiographic LVH. Maximum QT intervals (QTm), rate-corrected maximum QT intervals (QTc) and QT dispersion (QTd) were measured or calculated from ECGs. Data are presented as mean ± s.d. Differences in QT parameters were sought between groups using Student’s t-tests.Results: No ethnic or gender differences in QT parameters achieved statistical significance. However there was a tendency for QTm and QTc to be prolonged in blacks compared with whites (443 ± 52 vs 421 ± 47; P = 0.08 and 480 ± 65 vs 463 ± 40: P = 0.24 respectively), and for QTc to be prolonged in females compared with males (479 ± 52 vs 461 ± 45 ms; P= 0.13).Conclusion: In small groups of matched hypertensives, no ethnic or gender differences in QT parameters achieved statistical significance. However, similar to findings in normotensives, QTc tended to be longer in hypertensive females than males. In hypertensives, we failed to confirm the finding that QTc is shorter in blacks than whites, as seen in US normotensives. Whether this represents a difference between hypertensives and normotensives, or between US and UK blacks requires further investigation. Whether the prognostic significance of QT parameters in hypertensives differs between different gender and ethnic groups needs to be established from prospective studies.

No evidence for a direct vasodilatory effect of celiprolol on human vasculature in vivo or in vitro.

Summary Celiprolol is reported to be a new cardioselective p blocker with novel ancillary properties including vasodilator effects. The purpose of this study was to investigate whether celiprolol possesses a direct vasodilatory effect on human vasculature in vivo and in vitro. We studied the in vivo effects of intra-arterial celiprolol (1–100 μg/min i.a.) on forearm blood flow (FBF). Forearm blood was measured by venous occlusion plethysmography. Possible vasorelaxant actions of celiprolol on human vascular smooth muscle were studied using segments of isolated human saphenous vein in vitro. The effect of celiprolol was investigated on resting tone or noradrenaline induced tone. Possible aradrenoceptor antagonist effects of celiprolol were assessed using celiprolol as an antagonist of BHT933 induced constriction. Celiprolol was without significant effect on FBF and failed to relax isolated saphenous vein segments preconstricted with noradrenaline. The weak α2-adrenoceptor antagonist action of celiprolol was demonstrable in human saphenous vein. This study does not provide evidence for a direct vasodilatory effect of celiprolol on human vasculature.