Sheila K Patel

Publications (28) View all

• Article: Emerging markers in cardiovascular disease: where does ACE fit in?

  Sheila K Patel, Elena Velkoska, Louise M Burrell
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  ABSTRACT: The renin angiotensin system plays a major role in the pathophysiology of cardiovascular disease (CVD). The enzyme angiotensin converting enzyme (ACE) converts angiotensin (Ang) I into the vasoconstrictor Ang II, and was thought until recently to be the main effector of the system. The enzyme ACE2, discovered in 2000, can counterbalance the effects of ACE through degradation of Ang II, and generation of Ang 1-7. ACE2 is abundantly expressed in the heart and localised to endothelial cells of coronary vessels and smooth muscle cells. Its catalytically active ectodomain undergoes shedding, resulting in ACE2 in the circulation. There are 10 studies to date that have measured circulating ACE2 activity in man. These included healthy subjects, and those with heart failure, type 1 diabetes, implantable cardioverter/defibrillator, elderly subjects undergoing emergency orthopaedic surgery, and kidney transplant patients. The results suggest that circulating ACE2 activity may be a marker of CVD, with low levels in healthy individuals, and increased levels in those with CV risk factors or disease. Whether increased plasma ACE2 activity reflects increased synthesis from tissue ACE2 mRNA, or increased shedding of tissue ACE2, remains to be determined. ACE2 is located on the X chromosome, and circulating ACE2 levels are higher in men compared to women. Large clinical studies in CVD are needed to more precisely clarify the role of ACE2 as a biomarker of CVD, determine the prognostic significance of circulating ACE2 activity and assess whether the measurement of ACE2 will improve CVD risk prediction. © 2013 The Authors Clinical and Experimental Pharmacology and Physiology © 2013 Wiley Publishing Asia Pty Ltd.
  Clinical and Experimental Pharmacology and Physiology 02/2013; · 1.85 Impact Factor
• Source

  Available from: Louise M Burrell

  Article: The ACE2 gene: its potential as a functional candidate for cardiovascular disease.

  Louise M Burrell, Stephen B Harrap, Elena Velkoska, Sheila K Patel
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  ABSTRACT: The RAS (renin-angiotensin system) plays an important role in the pathophysiology of CVD (cardiovascular disease), and RAS blockade is an important therapeutic strategy in the management of CVD. A new counterbalancing arm of the RAS is now known to exist in which ACE (angiotensin-converting enzyme) 2 degrades Ang (angiotensin) II, the main effector of the classic RAS, and generates Ang-(1-7). Altered ACE2 expression is associated with cardiac and vascular disease in experimental models of CVD, and ACE2 is increased in failing human hearts and atherosclerotic vessels. In man, circulating ACE2 activity increases with coronary heart disease, as well as heart failure, and a large proportion of the variation in plasma ACE2 levels has been attributed to hereditary factors. The ACE2 gene maps to chromosome Xp22 and this paper reviews the evidence associating ACE2 gene variation with CVD and considers clues to potential functional ACE2 variants that may alter gene expression or transcriptional activity. Studies to date have investigated ACE2 gene associations in hypertension, left ventricular hypertrophy and coronary artery disease, but the results have been inconsistent. The discrepancies may reflect the sample size of the studies, the gender or ethnicity of subjects, the cardiovascular phenotype or the ACE2 SNP investigated. The frequent observation of apparent sex-dependence might be of special importance, if confirmed. As yet, there are no studies to concurrently assess ACE2 gene polymorphisms and circulating ACE2 activity. Large-scale carefully conducted clinical studies are urgently needed to clarify more precisely the potential role of ACE2 in the CVD continuum.
  Clinical Science 01/2013; 124(2):65-76. · 4.61 Impact Factor
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  Available from: Louise M Burrell

  Article: Age-dependent regulation of renal vasopressin V(1A) and V(2) receptors in rats with genetic hypertension: implications for the treatment of hypertension.

  Louise M Burrell, John Risvanis, Rachael G Dean, Sheila K Patel, Elena Velkoska, Colin I Johnston
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  ABSTRACT: The role of arginine vasopressin (AVP) as a hypertensive hormone remains controversial. We have previously reported that intervention with a V(1A) receptor antagonist in 6-week-old prehypertensive spontaneously hypertensive rats (SHR) for 4 weeks attenuated the subsequent development of hypertension in adult SHR. This study assessed the age-dependent regulation of plasma AVP levels and kidney V(1A) and V(2) receptor expression during the development of hypertension in SHR and in normotensive Sprague Dawley rats. Systolic blood pressure (SBP), plasma AVP, and plasma renin activity (PRA) and kidney V(1A) and V(2) receptor expression were assessed. SHR were studied at three ages: prehypertensive (6 weeks), developed hypertension (10 weeks), and established hypertension (16 weeks). SBP increased with age in SHR (P < .01) and both plasma AVP (P < .01) and PRA (P < .05) were increased in 10-week-old SHR. Renal medulla V(1A) receptor gene expression decreased in 10-week and 16-week-old SHR (P < .01), with a reduction in V(1A) receptor protein in the inner medulla of 16-week-old SHR (P < .05) compared with young SHR. There was no change in V(2) receptor expression during the development of hypertension. In normotensive rats, plasma AVP, PRA, and kidney V(1A) and V(2) receptor expression were unchanged over time. These data suggest that in SHR, activation of plasma AVP and the renal V(1A) receptor occurs during developing hypertension, with downregulation when hypertension is established. The use of V(1A) receptor antagonists in prehypertension may provide a unique opportunity for the prevention of hypertension in high-risk individuals.
  Journal of the American Society of Hypertension (JASH) 12/2012;
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  Available from: Elena Velkoska

  Article: Combination renin-angiotensin system blockade and angiotensin-converting enzyme 2 in experimental myocardial infarction: implications for future therapeutic directions.

  Luke J Burchill, Elena Velkoska, Rachael G Dean, Karen Griggs, Sheila K Patel, Louise M Burrell
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  ABSTRACT: The RAS (renin-angiotensin system) is activated after MI (myocardial infarction), and RAS blockade with ACEis [ACE (angiotensin-converting enzyme) inhibitors] or ARBs (angiotensin receptor blockers) slows but does not completely prevent progression to heart failure. Cardiac ACE is increased after MI and leads to the formation of the vasoconstrictor AngII (angiotensin II). The enzyme ACE2 is also activated after MI and degrades AngII to generate the vasodilator Ang-(1-7) [angiotensin-(1-7)]. Overexpression of ACE2 offers cardioprotective effects in experimental MI, but there is conflicting evidence as to whether the benefits of ACEis and ARBs are mediated through increasing ACE2 after MI. In the present study, we assessed the effect of an ACEi and ARB, alone and in combination, on cardiac ACE2 in a rat MI model. MI rats received vehicle, ACEi (ramipril; 1 mg/kg of body weight), ARB (valsartan; 10 mg/kg of body weight) or combination (ramipril at 1 mg/kg of body weight and valsartan at 10 mg/kg of body weight) orally for 28 days. Sham-operated rats were also studied and received vehicle alone. MI increased LV (left ventricular) mass (P<0.0001), impaired cardiac contractility (P<0.05) and activated cardiac ACE2 with increased gene (P<0.05) and protein expression (viable myocardium, P<0.05; border zone, P<0.001; infarct, P<0.05). Ramipril and valsartan improved remodelling (P<0.05), with no additional effect of dual therapy. Although ramipril inhibited ACE, and valsartan blocked the angiotensin receptor, neither treatment alone nor in combination augmented cardiac ACE2 expression. These results suggest that the cardioprotective effects of ramipril and valsartan are not mediated through up-regulation of cardiac ACE2. Strategies that do augment ACE2 after MI may be a useful addition to standard RAS blockade after MI.
  Clinical Science 06/2012; 123(11):649-58. · 4.61 Impact Factor
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  Available from: Elena Velkoska

  Article: The CTGF gene -945 G/C polymorphism is not associated with cardiac or kidney complications in subjects with type 2 diabetes.

  Sheila K Patel, Bryan Wai, Richard J Macisaac, Sharon Grant, Elena Velkoska, Michelle Ord, Sianna Panagiotopoulos, George Jerums, Piyush M Srivastava, Louise M Burrell
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  ABSTRACT: Connective tissue growth factor (CTGF) has been implicated in the cardiac and kidney complications of type 2 diabetes, and the CTGF -945 G/C polymorphism is associated with susceptibility to systemic sclerosis, a disease characterised by tissue fibrosis. This study investigated the association of the CTGF -945 G/C promoter variant with cardiac complications (left ventricular (LV) hypertrophy (LVH), diastolic and systolic dysfunction) and chronic kidney disease (CKD) in type 2 diabetes. The CTGF -945 G/C polymorphism (rs6918698) was examined in 495 Caucasian subjects with type 2 diabetes. Cardiac structure and function were assessed by transthoracic echocardiography. Kidney function was assessed using estimated glomerular filtration rate (eGFR) and albuminuria, and CKD defined as the presence of kidney damage (decreased kidney function (eGFR <60 ml/min/1.73 m2) or albuminuria). The mean age ± SD of the cohort was 62 ± 14 years, with a body mass index (BMI) of 31 ± 6 kg/m2 and median diabetes duration of 11 years [25th, 75th interquartile range; 5, 18]. An abnormal echocardiogram was present in 73% of subjects; of these, 8% had LVH alone, 74% had diastolic dysfunction and 18% had systolic ± diastolic dysfunction. CKD was present in 42% of subjects. There were no significant associations between the CTGF -945 G/C polymorphism and echocardiographic parameters of LV mass or cardiac function, or kidney function both before and after adjustment for covariates of age, gender, BMI, blood pressure and hypertension. CTGF -945 genotypes were not associated with the cardiac complications of LVH, diastolic or systolic dysfunction, nor with CKD. In Caucasians with type 2 diabetes, genetic variation in the CTGF -945 G/C polymorphism is not associated with cardiac or kidney complications.
  Cardiovascular Diabetology 04/2012; 11:42. · 3.35 Impact Factor