A M Heagerty

The University of Manchester, Manchester, England, United Kingdom

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Publications (176)1210.6 Total impact

  • Heart (British Cardiac Society) 06/2015; 101(Suppl 4):A99-A100. DOI:10.1136/heartjnl-2015-308066.176 · 6.02 Impact Factor
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    ABSTRACT: Perivascular adipose tissue (PVAT) has been shown by various studies to have an anti-contractile effect on the arteries it surrounds. The mechanism by which PVAT exerts its anti-contractile effect is not well understood, and is likely to involve the release of PVAT-derived relaxing factors (PVRF) such as adiponectin, that causes hyperpolarisation and relaxation of the vascular smooth muscle. The PVAT anti-contractile effect is lost in obesity, therefore understanding this mechanism is vital for creating novel treatments of obesity-related hypertension. We propose that the mechanism involves stimulation of adipocyte β3-adrenoceptors in PVAT.
    Heart (British Cardiac Society) 06/2014; 100(Suppl 3):A102. DOI:10.1136/heartjnl-2014-306118.181 · 6.02 Impact Factor
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    ABSTRACT: Perivascular adipose tissue (PVAT) exerts an anticontractile effect that is lost in obesity. A recent study reported that bariatric surgery can reverse the damaging effects of obesity on PVAT function with accompanying reduction in systolic blood pressure. However, PVAT function has not previously been characterised following weight loss induced by caloric restriction, which is often the first line treatment for obesity. This study investigated the role of PVAT in control of vascular function in rat models of diet-induced obesity and weight loss.
    Heart (British Cardiac Society) 06/2014; 100(Suppl 3):A111. DOI:10.1136/heartjnl-2014-306118.202 · 6.02 Impact Factor
  • Atherosclerosis; 12/2013
  • Heart (British Cardiac Society) 05/2013; 99(Suppl 2):A105-A105. DOI:10.1136/heartjnl-2013-304019.186 · 6.02 Impact Factor
  • Heart (British Cardiac Society) 05/2013; 99(Suppl 2):A108-A108. DOI:10.1136/heartjnl-2013-304019.194 · 6.02 Impact Factor
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    ABSTRACT: BACKGROUND AND PURPOSE Perivascular adipose tissue (PVAT) releases adipocyte-derived hyperpolarizing factors (ADHFs) that may partly act by opening myocyte K+ channels. The present study in rat and mouse mesenteric arteries aimed to identify the myocyte K+ channel activated by PVAT and to determine whether adiponectin contributed to the hyperpolarizing effects of PVAT. EXPERIMENTAL APPROACH Myocyte membrane potential was recorded from de-endothelialized, non-contracted rat and mouse mesenteric arteries in the presence and absence of PVAT. KEY RESULTS The beta(3)-adrenoceptor agonist, CL-316,243 (10 mM), generated PVAT-dependent, iberiotoxin-sensitive myocyte hyperpolarizations resulting from BKCa channel opening and which were partially blocked by L-NMMA (100 mu M). Adiponectin (5 mu g.mL(-1)) also produced iberiotoxin-sensitive hyperpolarizations in PVAT-denuded arterioles. Activation of myocyte AMP-activated protein kinase (AMPK) using 5 mM A-769662 also induced BKCa-mediated hyperpolarizations. Dorsomorphin abolished hyperpolarizations to CL-316,243, adiponectin and A-769662. In vessels from Adipo(-/-) mice, hyperpolarizations to CL-316,243 were absent whereas those to A-769662 and adiponectin were normal. In rat vessels, adipocyte-dependent hyperpolarizations were blocked by glibenclamide and clotrimazole but those to NS1619 (33 mu M) were unaltered. CONCLUSIONS AND IMPLICATIONS Under basal, non-contracted conditions, beta(3)-adrenoceptor stimulation of PVAT releases an ADHF, which is probably adiponectin. This activates AMPK to open myocyte BKCa channels indirectly and additionally liberates NO, which also contributes to the observed PVAT-dependent myocyte hyperpolarizations. Clotrimazole and glibenclamide each reversed hyperpolarizations to adiponectin and A-769662, suggesting the involvement of myocyte TRPM4 channels in the ADHF-induced myocyte electrical changes mediated via the opening of BKCa channels.
    British Journal of Pharmacology 03/2013; 169(7). DOI:10.1111/bph.12157 · 4.99 Impact Factor
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    Artery Research 12/2012; 6(4):145. DOI:10.1016/j.artres.2012.09.019
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    ABSTRACT: Treatment response in late-life depression has been linked to cerebrovascular disease notably via the vascular depression hypothesis. This study investigated the relationship between endothelial function and atherosclerosis and treatment response to antidepressant monotherapy. Twenty five patients with late-life depression were compared with 21 non-depressed control subjects in a case control study. Nine of the depressed subjects were responders to antidepressant monotherapy and 16 were not. Vascular measures included assessment of carotid intima media thickness (IMT) representing atherosclerosis and biopsied small artery dilatation to acetylcholine to assess endothelial function in a subset of subjects. There were no group differences in vascular risks or sociodemographic variables. There was a significant group difference (responders versus non-responders versus controls) on both IMT and endothelial function (p < 0.01 and p < 0.05, respectively) with a significant difference between controls and non-responders (p < 0.001) on IMT and between controls and responders (p < 0.05) and control versus non-responders (p < 0.05) on endothelial function but no significant difference between responders and non-responders. On both IMT and endothelial function, there was a gradient across groups, with control subjects having best vascular structure or function, non-responders worse and responders in-between. The results are consistent with a hypothesis that poorer antidepressant response in later life depressive disorder may be linked to an underlying vascular dysfunction and pathology. The study is small, and the results require replication but if confirmed, trials with vasoprotective medication aimed at improving vascular function in order to alter the prognosis of late-life depression would be a rational development.
    International Journal of Geriatric Psychiatry 09/2012; 27(9):967-73. DOI:10.1002/gps.2811 · 3.09 Impact Factor
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    ABSTRACT: The last few decades have witnessed a global rise in adult obesity of epidemic proportions. The potential impact of this is emphasized when one considers that body mass index (BMI) is a powerful predictor of death, type 2 diabetes (T2DM) and cardiovascular (CV) morbidity and mortality [1, 2]. Similarly we have witnessed a parallel rise in the incidence of atrial fibrillation (AF), the commonest sustained cardiac arrhythmia, which is also a significant cause of cardiovascular morbidity and mortality. Part of this increase is attributable to advances in the treatment of coronary heart disease (CHD) and heart failure (HF) improving life expectancy and consequently the prevalence of AF. However, epidemiological studies have demonstrated an independent association between obesity and AF, possibly reflecting common pathophysiology and risk factors for both conditions. Indeed, weight gain and obesity are associated with structural and functional changes of the cardiovascular system including left atrial and ventricular remodeling, haemodynamic alterations, autonomic dysfunction, and diastolic dysfunction. Moreover, diabetic cardiomyopathy is characterized by an adverse structural and functional cardiac phenotype which may predispose to the development of AF [3]. In this review, we discuss the pathophysiological and mechanistic relationships between obesity, diabetes and AF, and the challenges posed in the management of this high-risk group of individuals.
    Current Cardiology Reviews 08/2012; 8(4). DOI:10.2174/157340312803760749
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    ABSTRACT: Fat cells or adipocytes are distributed ubiquitously throughout the body and are often regarded purely as energy stores. However, recently it has become clear that these adipocytes are engine rooms producing large numbers of metabolically active substances with both endocrine and paracrine actions. White adipocytes surround almost every blood vessel in the human body and are collectively termed perivascular adipose tissue (PVAT). It is now well recognized that PVAT not only provides mechanical support for any blood vessels it invests, but also secretes vasoactive and metabolically essential cytokines known as adipokines, which regulate vascular function. The emergence of obesity as a major challenge to our healthcare systems has contributed to the growing interest in adipocyte dysfunction with a view to discovering new pharmacotherapeutic agents to help rescue compromised PVAT function. Very few PVAT studies have been carried out on human tissue. This review will discuss these and the hypotheses generated from such research, as well as highlight the most significant and clinically relevant animal studies showing the most pharmacological promise. LINKED ARTICLES: This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3.
    British Journal of Pharmacology 05/2011; 165(3):670-82. DOI:10.1111/j.1476-5381.2011.01479.x · 4.99 Impact Factor
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    ABSTRACT: To determine the population distribution of cardiovascular risk in eight low- and middle-income countries and compare the cost of drug treatment based on cardiovascular risk (cardiovascular risk thresholds ≥ 30%/≥ 40%) with single risk factor cutoff levels. Using World Health Organization (WHO) and the International Society of Hypertension risk prediction charts, cardiovascular risk was categorized in a cross-sectional study of 8,625 randomly selected people aged 40-80 years (mean age, 54.6 years) from defined geographic regions of Nigeria, Iran, China, Pakistan, Georgia, Nepal, Cuba, and Sri Lanka. Cost estimates for drug therapy were calculated for three countries. A large fraction (90.0-98.9%) of the study population has a 10-year cardiovascular risk <20%. Only 0.2-4.8% are in the high-risk categories (≥ 30%). Adopting a total risk approach and WHO guidelines recommendations would restrict unnecessary drug treatment and reduce the drug costs significantly. Adopting a total cardiovascular risk approach instead of a single risk factor approach reduces health care expenditure by reducing drug costs. Therefore, limited resources can be more efficiently used to target high-risk people who will benefit the most. This strategy needs to be complemented with population-wide measures to shift the cardiovascular risk distribution of the whole population.
    Journal of clinical epidemiology 04/2011; 64(12):1451-62. DOI:10.1016/j.jclinepi.2011.02.001 · 5.48 Impact Factor
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    ABSTRACT: Following publication of the National Institute of Clinical Excellence (NICE) Guidelines in 2006, the use of β-blockers as first-line therapy in hypertension has been somewhat controversial. However, a recent reappraisal of the European Society of Hypertension guidelines highlights that these agents exhibit similar BP lowering efficacy to other classes of agents, prompting a re-examination of the utility of these agents in various patient populations. The authors felt that it is important to address this controversy and provide an Asian perspective on the place of β-blockers in current clinical practice and the benefits of β-blockade in selected patient populations. In addition to their use as a potential first-line therapy in uncomplicated hypertension, β-blockers have a particular role in patients with hypertension and comorbidities such as heart failure or coronary artery disease, including those who had a myocardial infarction. One advantage which β-blockers offer is the additional protective effects in patients with prior cardiovascular events. Some of the disadvantages attributed to β-blockers appear more related to the older drugs in this class and further appraisal of the efficacy and safety profile of newer β-blockers will lend support to the current guideline recommendations in Asian countries and encourage increased appropriate use of β-blockade in current clinical practice within Asia.
    Current Medical Research and Opinion 03/2011; 27(5):1021-33. DOI:10.1185/03007995.2011.562884 · 2.37 Impact Factor
  • F. Lynch, S. Withers, A. Heagerty
    Journal of Hypertension 01/2011; 29:e9-e10. DOI:10.1097/00004872-201106001-00026 · 4.22 Impact Factor
  • Journal of Hypertension 01/2011; 29:e15-e16. DOI:10.1097/00004872-201106001-00042 · 4.22 Impact Factor
  • Journal of Hypertension 01/2011; 29:e170. DOI:10.1097/00004872-201106001-00437 · 4.22 Impact Factor
  • Journal of Hypertension 01/2011; 29:e11. DOI:10.1097/00004872-201106001-00031 · 4.22 Impact Factor
  • Artery Research 12/2010; 4(4):168-168. DOI:10.1016/j.artres.2010.10.079
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    ABSTRACT: We tested the hypothesis that aldosterone causes a loss of the normal anticontractile function of healthy fat via a hypoxia-related pathway, which can be rescued using spironolactone. Healthy rat mesenteric arteries ( approximately 250%muM diameter) and perivascular fat were investigated using wire myography and Perl's Prussian blue staining for activated macrophages. The effects of aldosterone%+/-spironolactone were assessed after incubation for 10 min and 3 h, and experimental hypoxia (95% N(2)/5% CO(2)) for 2.5 h. Contractile responses were calculated as a percentage of KCl contraction and expressed as mean+/-SEM. Macrophage activation was expressed semiquantitatively and expressed as macrophage abundance values (MAV). The anticontractile capacity of healthy fat was lost upon incubation with aldosterone (5 nM) (fat: 90+/-4% n=36, fat+10 min aldosterone: 165+/-5% n=25, fat+3 h aldosterone 172%+/-12% n=7) and was associated with an increase in activated macrophages (immediately fixed: 2.2+/-0.5% n=5 vs 10 min aldosterone: 3.8+/-0.4% n=5, p=NS; immediately fixed: 2.2+/-0.5% n=5 vs 3 h aldosterone: 4.7+/-0.3% n=5, p=0.0313). Spironolactone (10%muM) restored anticontractile activity after incubation for 3 h only (3 h:111+/-4% p<0.05, n=5) and caused a significant reduction in macrophage activation (3.0+/-1.0%, n=5). As for aldosterone, hypoxia caused an increase in contractility (149+/-17% n=15) and macrophage activation (5.5+/-0.5% n=5), which was reversed upon incubation with spironolactone (contractility: 120+/-12% n=5;MAV: 3.3+/-0.8%, n=3, p=0.500). Aldosterone ameliorates the anticontractile capacity of healthy fat by a common pathway to hypoxia, which correlates with an increase in the number of activated macrophages within adipose tissue. Spironolactone can restore the effect of hypoxia on contractility and macrophage activation in the absence of aldosterone.
    Heart (British Cardiac Society) 09/2010; 96(17):e19. DOI:10.1136/hrt.2010.205781.35 · 6.02 Impact Factor
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    ABSTRACT: Introduction In health, perivascular adipose tissue (PVAT) has an anticontractile function on adjacent small arteries. We have recently shown that adipocyte hypoxia and inflammation in obesity attenuates PVAT anticontractile function. In animals, PVAT function has only been examined in genetic models of obesity, which are rare in clinical practice. Methods 11 Sprague-Dawley rats were fed a high-fat diet (HF; n=11) over 15-18 weeks. Seven control animals received a normal diet. Weight and blood pressure were monitored. The HF rats were split into two groups: (a) diet-induced obese (DIO; n=6): significantly gained weight after a 10-week period, and diet resistant (DR; n=5): weight comparable to control group. Mesenteric arteries were studied using wire myography with construction of cumulative dose responses to noradrenaline, with and without PVAT intact. Results The weight and systolic blood pressure for DIO were significantly increased compared with the controls (systolic BP: control: 124%+/-4; DR: 138%+/-8; DIO: 150%+/-3 p<0.05). The contractile responses of vessels with intact PVAT were significantly different from vessels without PVAT in control (p<0.001-multiple ANOVA) and DR (p=0.001-multiple ANOVA) groups. In DIO, the dose-response curves for vessels with intact PVAT and without PVAT were not significantly different (p=0.210-multiple ANOVA). Conclusion The anticontractile function of PVAT was preserved in DR, but partially lost in DIO. This suggests that weight gain rather than diet itself initiates PVAT damage, which is associated with hypertension. This is the first animal model of environmental obesity in which PVAT function has been studied.
    Heart (British Cardiac Society) 09/2010; 96(17):e17. DOI:10.1136/hrt.2010.205781.29 · 6.02 Impact Factor

Publication Stats

5k Citations
1,210.60 Total Impact Points


  • 1995–2014
    • The University of Manchester
      • • Faculty of Life Sciences
      • • School of Biomedicine
      Manchester, England, United Kingdom
  • 2007–2011
    • Central Manchester University Hospitals NHS Foundation Trust
      • Division of Medicine
      Manchester, England, United Kingdom
  • 1986–1995
    • Aarhus University
      • Department of Pharmacology
      Aars, Region North Jutland, Denmark
  • 1982–1991
    • University of Leicester
      • School of Medicine
      Leiscester, England, United Kingdom
  • 1987
    • University of Vienna
      Wien, Vienna, Austria