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ABSTRACT: The role of high sensitivity troponin T (hs-TnT) in the convalescence phase after an acute coronary syndrome (ACS) is unknown. The authors aim to assess the prognostic utility of a single hs-TnT level at 7-week post-ACS. Second, the authors evaluated whether any serial changes in hs-TnT between the index admission and 7 weeks post-ACS had any link with the prognosis. Third, the authors assessed whether the prognostic utility of hs-TnT is independent of various echocardiographic abnormalities.
The authors measured hs-TnT levels in 326 consecutive patients at 7 weeks after an ACS event. The composite end point of death from any cause or acute myocardial infarction was evaluated over a median duration of 30 months.
A high 7-week hs-TnT (>14 ng/l) predicted adverse clinical outcomes independent of conventional risk factors, left ventricular dysfunction and left ventricular hypertrophy on echocardiography (adjusted RR: 2.69 (95% CI 1.45 to 5.00)). Patients with persistent hs-TnT elevation at 7 weeks were also at an increased risk of cardiovascular events compared with those with an initial high hs-TnT which then normalised (unadjusted RR 3.39 (95% CI 2.02 to 5.68)).
The authors have demonstrated the prognostic utility of a single 7-week hs-TnT measurement in routine ACS patients and that it could be used to assist medium term risk stratification in this patient cohort. In addition, the authors also showed that hs-TnT predicted long-term adverse prognosis independent of various echo parameters. Future studies should evaluate whether tailoring specific treatment interventions to higher risk individuals as identified by an elevated hs-TnT during the convalescence phase of ACS would improve clinical outcomes.
Heart (British Cardiac Society) 06/2012; 98(15):1160-5. · 4.22 Impact Factor
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Laura Kennedy,
Mahesh Pauriah,
Valerie Godfrey,
Jacqueline Howie,
Helen Dennis,
Daniel Crowther, Allan Struthers,
Catharine Goddard,
Giora Feuerstein,
Chim Lang,
Gino Miele
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ABSTRACT: Background: Technical advances in the collection of clinical material, such as laser capture microdissection and cell sorting, provide the advantage of yielding more refined and homogenous populations of cells. However, these attractive advantages are counter balanced by the significant difficulty in obtaining adequate nucleic acid yields to allow transcriptomic analyses. Established technologies are available to carry out global transcriptomics using nanograms of input RNA, however, many clinical samples of low cell content would be expected to yield RNA within the picogram range. To fully exploit these clinical samples the challenge of isolating adequate RNA yield directly and generating sufficient microarray probes for global transcriptional profiling from this low level RNA input has been addressed in the current report. We have established an optimised RNA isolation workflow specifically designed to yield maximal RNA from minimal cell numbers. This procedure obtained RNA yield sufficient for carrying out global transcriptional profiling from vascular endothelial cell biopsies, clinical material not previously amenable to global transcriptomic approaches. In addition, by assessing the performance of two linear isothermal probe generation methods at decreasing input levels of good quality RNA we demonstrated robust detection of a class of low abundance transcripts (GPCRs) at input levels within the picogram range, a lower level of RNA input (50 pg) than previously reported for global transcriptional profiling and report the ability to interrogate the transcriptome from only 10 pg of input RNA. By exploiting an optimal RNA isolation workflow specifically for samples of low cell content, and linear isothermal RNA amplification methods for low level RNA input we were able to perform global transcriptomics on valuable and potentially informative clinically derived vascular endothelial biopsies here for the first time. These workflows provide the ability to robustly exploit ever more common clinical samples yielding extremely low cell numbers and RNA yields for global transcriptomics.
PLoS ONE 01/2011; 6(3):e17625. · 4.09 Impact Factor
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ABSTRACT: B-type natriuretic peptide (BNP) is a natriuretic peptide released primarily by ventricular myocytes in response to various physiological and pathological stimuli. In addition to its established diagnostic role in patients with heart failure, a growing body of evidence suggests that raised levels of BNP in the absence of heart failure can indicate myocardial ischaemia. This appears to be the case in patients with symptomatic, and even asymptomatic coronary artery disease (CAD). In this review, we discuss the current evidence supporting the role of BNP as a simple marker of cardiac ischaemia and CAD. We also propose some therapeutic interventions that may be useful when BNP detects silent myocardial ischaemia.
The British Journal of Diabetes & Vascular Disease 01/2010; 10(2):78-82.
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ABSTRACT: Vitamin D insufficiency has been linked to hypertension and cardiovascular events in observational studies. It is unclear whether vitamin D supplementation can reduce blood pressure, and, if so, by how much.
We performed a systematic review and meta-analysis to examine whether vitamin D reduces blood pressure. Databases including MEDLINE, EMBASE, the Cumulative Index to Nursing and Allied Health Literature and the Cochrane library were searched, supplemented by searches of grey literature, unpublished trials and references from included studies. Studies were assessed by two reviewers independently according to a prespecified protocol. Interventions included activated vitamin D, unactivated vitamin D2 and D3 and ultraviolet B radiation.
Eleven randomized, controlled trials fulfilled the inclusion criteria. Studies were small and of variable methodological quality. Mean baseline blood pressure was more than 140/90 mmHg in eight studies. Meta-analysis of these eight studies showed a nonsignificant reduction in systolic blood pressure in the vitamin D group compared with placebo [-3.6 mmHg, 95% confidence interval (CI) -8.0 to 0.7]. A small, statistically significant reduction was seen in diastolic blood pressure (-3.1 mmHg, 95% CI -5.5 to -0.6). Subgroup analysis suggested that unactivated vitamin D produced a greater fall in systolic blood pressure than activated vitamin D (-6.2 mmHg, 95% CI -12.32 to -0.04, vs. +0.7 mmHg, 95% CI -4.8 to 6.2). No reduction in blood pressure was seen in studies examining patients who were normotensive at baseline.
We found weak evidence to support a small effect of vitamin D on blood pressure in studies of hypertensive patients.
Journal of hypertension 08/2009; 27(10):1948-54. · 4.02 Impact Factor
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Journal of the American College of Cardiology 07/2009; 53(25):2405. · 14.16 Impact Factor
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ABSTRACT: CNP (C-type natriuretic peptide) is a vasodilatory peptide produced by vascular endothelium and the human heart with a short half-life. CNP has been identified within the human kidney; however, few results are available on whether the human kidney is a systemic source of CNP. The aim of the present study was to establish whether CNP is secreted by the human kidney and if synthesis is blunted in CHF (chronic heart failure). A total of 20 male subjects (age, 57+/-2 years; mean+/-S.E.M.) undergoing CHF assessment (n=13) or investigation of paroxysmal supraventricular arrhythmia (normal left ventricular function in sinus rhythm during procedure) (n=7) were recruited. Renal CNP production was determined from concomitant plasma concentrations in the aorta and renal vein. When considering all subjects, a significant step-up in plasma CNP was found from the aorta to renal vein (3.0+/-0.3 compared with 8.3+/-2.4 pg/ml respectively; P=0.0045). The mean increase in CNP was 5.3+/-2.4 pg/ml (range, -0.9 to +45.3 pg/ml). In patients with CHF, the aortic concentration was 3.3+/-0.4 pg/ml compared with a renal vein concentration of 4.3+/-0.6 pg/ml (P=0.11). In those with normal left ventricular function, the respective values were 2.5+/-0.5 and 15.7+/-6.0 pg/ml (P=0.01). In conclusion, CNP is synthesized and secreted into the circulation by the normal human kidney, where it may have paracrine actions. Net renal secretion of CNP appears to be blunted in patients with CHF.
Clinical Science 06/2009; 118(1):71-7. · 4.61 Impact Factor
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ABSTRACT: Vascular oxidative stress has been shown to be a potent factor in the pathophysiology of endothelial dysfunction. Despite current optimal evidence-based therapy, mortality from various cardiovascular disorders remains high. The search for newer, novel ways of attenuating endothelial dysfunction has yielded several new and exciting possibilities, one of which is the manipulation of urate levels using xanthine oxidase inhibitors. Agents such as allopurinol have shown marked improvements in vascular endothelial function in various cohorts at risk of cardiovascular events. Most of the evidence so far comes from smaller mechanistic studies. The few large randomized controlled trials have failed to show any significant mortality benefit using these agents. This article highlights the potential avenues of further research such as dose-response, and the potential for these agents to regress left ventricular hypertrophy. The role of newer agents such as febuxostat and oxypurinol are discussed as well as potential reasons why some of the current newer agents have failed to live up to the promising early-phase data. It is crucial that these remaining questions surrounding urate, xanthine oxidase and the role of various agents that affect this important oxidative stress-generating system are answered, and therefore these promising agents should not be discarded prematurely.
Therapeutics and Clinical Risk Management 01/2009; 5:799-803.
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ABSTRACT: Improved understanding of the adverse pharmacological properties of aldosterone has prompted investigation of the clinical benefits of blocking aldosterone at the receptor level. This article reviews the pharmacology, clinical efficacy, and tolerability of the two available blocking agents, spironolactone and eplerenone. A Medline search identified clinical studies assessing spironolactone and eplerenone. Priority was given to large, well-controlled, clinical trials and comparative studies. Pharmacological differences between spironolactone and eplerenone include lower affinity of eplerenone for progesterone, androgen, and glucocorticoid receptors; more consistently demonstrated nongenomic properties for eplerenone; and the presence of long-acting metabolites for spironolactone. Both agents effectively treat hypertension and heart failure but comparisons are complicated by the deficiency of head-to-head trials and differences between patient populations. There are differences in the tolerability profiles; spironolactone is associated with dose-dependent sexual side effects. Both agents produce dose-dependent increases in potassium concentrations, although the effect with spironolactone appears to be greater when both agents are administered at recommended doses. Choice of a specific agent should be based on individual patient issues, such as the nature of heart failure and patient concerns about adverse events.
Clinical Cardiology 05/2008; 31(4):153-8. · 2.15 Impact Factor
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ABSTRACT: Improved understanding of the adverse pharmacological properties of aldosterone has prompted investigation of the clinical benefits of blocking aldosterone at the receptor level. This article reviews the pharmacology, clinical efficacy, and tolerability of the two available blocking agents, spironolactone and eplerenone. A Medline search identified clinical studies assessing spironolactone and eplerenone. Priority was given to large, well-controlled, clinical trials and comparative studies. Pharmacological differences between spironolactone and eplerenone include lower affinity of eplerenone for progesterone, androgen, and glucocorticoid receptors; more consistently demonstrated nongenomic properties for eplerenone; and the presence of long-acting metabolites for spironolactone. Both agents effectively treat hypertension and heart failure but comparisons are complicated by the deficiency of head-to-head trials and differences between patient populations. There are differences in the tolerability profiles; spironolactone is associated with dose-dependent sexual side effects. Both agents produce dose-dependent increases in potassium concentrations, although the effect with spironolactone appears to be greater when both agents are administered at recommended doses. Choice of a specific agent should be based on individual patient issues, such as the nature of heart failure and patient concerns about adverse events. Copyright © 2008 Wiley Periodicals, Inc.
Clinical Cardiology 03/2008; 31(4):153 - 158. · 2.15 Impact Factor
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ABSTRACT: Brain natriuretic peptide (BNP) or N-terminal pro-BNP (N-BNP) now appears to be the best independent predictor of cardiovascular mortality over and above the conventional ones like blood pressure. This may be because a high BNP/N-BNP is identifying any form of asymptomatic cardiac target organ damage (TOD) [especially silent ischaemia, left ventricular hypertrophy (LVH), left atrial dilatation/atrial fibrillation (LAD/AF) and LV systolic dysfunction (LVSD)]. There are strong hints that BNP/N-BNP will also identify those who are going to develop LVH, LAD/AF, and LVSD in a few years' time. Thus, the prospects are good that BNP/N-BNP could be used to identify 'pancardiac' TOD, even when it is silent and that this information could be 'harnessed' to improve primary prevention. BNP/N-BNP could become to the heart what microalbuminuria is to the kidneys, i.e. an indicator of early, silent TOD.
European Heart Journal 08/2007; 28(14):1678-82. · 10.48 Impact Factor
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ABSTRACT: To assess the role of the endothelial nitric oxide synthase (eNOS) gene variant as a risk factor for atherosclerosis we sought to investigate whether the Glu298Asp polymorphism of the eNOS gene is associated with functional changes in the endothelium in healthy volunteers.
Endothelial function was assessed in 68 normal volunteers (ages 18-44 years) by bilateral forearm venous occlusion plethysmography with intraarterial infusions of increasing doses of acetylcholine for endothelial-dependent vasodilation and, with sodium nitroprusside and verapamil for endothelial-independent vasodilation. Blood was genotyped by polymerase chain reaction and BanII digestion.
Asp homozygotes (TT) had a decreased vasodilatory response to acetylcholine [forearm blood flow (FBF) ratio between infused and control arm, 2.82 +/- 1.10] when compared to GG variant (FBF ratio to acetylcholine, 3.97 +/- 1.90, p= 0.04) and to a certain extent, the GT variant (FBF ratio to acetylcholine, 3.79 +/- 2.28, p= 0.07). There was no effect of eNOS genotype on the response to the endothelial-independent vasodilators-sodium nitroprusside and verapamil.
Our data show that carriage of the Asp298 variant of the eNOS gene is associated with a blunted endothelial-dependent vasodilation in healthy volunteers. These findings support a genetically determined modulation of endothelial dysfunction, a phenotype of early atherosclerosis in humans.
Cardiovascular Drug Reviews 02/2007; 25(3):280-8. · 5.21 Impact Factor
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ABSTRACT: Allopurinol has been shown to improve endothelial function in chronic heart failure. This study aimed to establish its mechanism of action and to construct a dose-response curve for the effect of allopurinol.
Two randomized, placebo-controlled, double-blind, crossover studies were performed for 1 month on patients with New York Heart Association Class II-III chronic heart failure, comparing 300 mg allopurinol, 600 mg allopurinol, and placebo for the first study and 1000 mg probenecid versus placebo in the second study. Endothelial function was assessed by standard forearm venous occlusion plethysmography. Allopurinol 600 mg/d significantly increased forearm blood flow response to acetylcholine compared with both allopurinol 300 mg/d and placebo (% change in forearm blood flow [mean+/-SEM]: 240.31+/-38.19% versus 152.10+/-18.21% versus 73.96+/-10.29%, P<0.001). For similar levels of urate lowering, the uricosuric agent probenecid had no effect on endothelial function. Sodium nitroprusside response was unchanged by all treatments. Vitamin C and acetylcholine coinfusion data showed that 600 mg/d allopurinol completely abolished the oxidative stress that was sensitive to high-dose vitamin C.
For the first time, we have shown that a steep dose-response relationship exists between allopurinol and its effect on endothelial function. We also showed that the mechanism of improvement in endothelial function with allopurinol lies in its ability to reduce vascular oxidative stress and not in urate reduction. The reduction in vascular oxidative stress was profound because high-dose allopurinol totally abolished the oxidative stress that was sensitive to the high-dose vitamin C that was used in this study.
Circulation 01/2007; 114(23):2508-16. · 14.74 Impact Factor
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ABSTRACT: Recent evidence points to a role for the renin-angiotensin-aldosterone system (RAAS) in the pathogenesis of atherosclerosis and its complications, including acute angina pectoris. Two large trials in heart failure have clearly demonstrated that blocking aldosterone improves mortality and that this benefit occurs over and above standard therapy with angiotensin-converting enzyme (ACE) inhibitors. The question that naturally arises from these landmark studies is whether aldosterone blockade would produce the same benefits in patients with coronary artery disease (CAD) but no heart failure. There are three reasons to believe this might be the case. Firstly, angiotensin II (Ang II) and aldosterone produce similar biological effects and Ang II withdrawal has been shown to benefit patients with angina; aldosterone blockade may therefore follow in the footsteps of ACE inhibitors, as it did in heart failure, and produce benefits in vascular patients without heart failure. Secondly, one of the main mechanisms which is thought to be responsible for the benefit of aldosterone blockade in the Randomised ALdactone Evaluation Study (RALES) and Eplerenone Post-AMI Heart Failure Survival Study (EPHESUS), is that it improves endothelial/vascular function and endothelial/vascular dysfunction is the fundamental abnormality in angina pectoris. Finally, aldosterone blockade has been shown to reduce atherosclerosis in animal studies of atherosclerosis without heart failure, which are analogous to CAD patients.
Journal of Renin-Angiotensin-Aldosterone System 04/2006; 7(1):20-30. · 2.44 Impact Factor
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ABSTRACT: It has been suggested that angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin II receptor blockers (ARBs) have a differential effect on brachial and aortic haemodynamics. This is why they seem to have beneficial effects that are beyond brachial blood pressure (BP) lowering. We aimed to investigate if this was the case with losartan when compared to atenolol. We also investigated the differential effect of losartan and atenolol on the prognostic marker, brain type natriuretic peptide (BNP).
We studied 17 patients who were similar to those in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Patients were randomised to receive four months of losartan and atenolol in a crossover fashion. Main outcome measures were BNP and Augmentation index (AIx), which gives an indication of central haemodynamics. Brachial pulse wave velocity (PWV) and time to reflected wave (Tr) were measured as an indication of vascular stiffness.
BNP was significantly lower on losartan than atenolol (p=0.007). AIx was lower on losartan than atenolol (p=0.03), however, this result was not significant when heart rate was considered as a covariate (p=0.09). Heart rate was significantly lower on atenolol than losartan (p=0.03). There was no difference between treatments for both brachial PWV and Tr (p=0.2 and p=0.99, respectively).
The benefits seen when losartan was compared to atenolol in the LIFE trial may be due to a reduction in BNP. We failed to detect a differential effect in central compared to peripheral haemodynamics when losartan was compared to atenolol.
Journal of Renin-Angiotensin-Aldosterone System 01/2006; 6(3):151-3. · 2.44 Impact Factor
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ABSTRACT: Interest in the renin-angiotensin-aldosterone system (RAAS) has increased since the development of angiotensin-converting enzyme (ACE) inhibitors. It has been discovered that the potential uses of this class of treatment extend far beyond their initial developmental role as antihypertensives, and they are now used routinely in the treatment of heart failure, nephropathy, myocardial infarction and diabetes. However, there is more to RAAS blockade than just inhibition of angiotensin II, and inhibition of aldosterone is becoming recognised as an additional therapeutic manoeuvre in chronic heart failure. Since inhibition of the RAAS at the level of ACE is now seen to be an important therapy in diabetes; the purpose of this article is to explore the potential benefits of additional aldosterone inhibition in Type 2 diabetes mellitus.
Journal of Renin-Angiotensin-Aldosterone System 10/2002; 3(3):150-5. · 2.44 Impact Factor
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ABSTRACT: Eighty-two patients aged ≥70 years with heart failure were randomized to a gentle, seated exercise program or to usual care. Six-minute walk distance and quality of life did not change between groups, but daily activity as measured by accelerometry increased in the exercise group relative to the control group.
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ABSTRACT: Background— Increased oxidative stress in chronic heart failure is thought to contribute to endothelial dysfunction. Xanthine oxidase produces oxidative stress and therefore we examined whether allopurinol improved endothelial dysfunction in chronic heart failure. Methods and Results— We performed a randomized, placebo-controlled, double-blind crossover study on 11 patients with New York Heart Association class II-III chronic heart failure, comparing 300 mg allopurinol daily (1 month) versus placebo. Endothelial function was assessed by standard forearm venous occlusion plethysmography with acetylcholine, nitroprusside, and verapamil. Plasma malondialdehyde levels were also compared to assess significant changes in oxidative stress. Allopurinol significantly increased the forearm blood flow response to acetylcholine (percentage change in forearm blood flow [mean±SEM]: 181±19% versus 120±22% allopurinol versus placebo; P=0.003). There were no significant differences in the forearm blood flow changes between the placebo and allopurinol treatment arms with regard to sodium nitroprusside or verapamil. Plasma malondialdehyde was significantly reduced with allopurinol treatment (346±128 nmol/L versus 461±101 nmol/L, allopurinol versus placebo; P=0.03), consistent with reduced oxidative stress with allopurinol therapy. Conclusions— We have shown that allopurinol improves endothelial dysfunction in chronic heart failure. This raises the distinct possibility that allopurinol might reduce cardiovascular events and even improve exercise capacity in chronic heart failure.
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ABSTRACT: Aims To test the hypothesis that urate predicts cardiac death after stroke independent of conventional risk factors of atherosclerosis, creatinine and diuretic use. Methods and Results Serum urate concentration was measured in an unselected cohort of 354 stroke survivors who were followed-up for a median of 2·8 years. Cardiac death was the primary end-point. Urate was associated with a statistically significant threefold increase in relative risk of cardiac death even after adjustment for other conventional risk factors. In the subgroup of patients who were not on diuretics, raised urate was associated with a 12-fold significant increase in relative risk of cardiac death after adjusting for renal function and other conventional risk factors. A urate concentration of greater than 0·31mmol.l⁻¹ was 78% sensitive at predicting cardiac death within 5 years after stroke, but was only 54% specific. If urate exceeded 0·38mmol.l⁻¹, specificity of predicting cardiac death within 5 years after stroke was 88%. Conclusions Elevated serum urate concentration may be used to stratify risk of future cardiac. Chief Scientist Office (Scottish Office) Tayside Health Board Tayside University Hospitals NHS Trust Tayside Primary Care NHS Trust University of Dundee
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ABSTRACT: Objective: To evaluate the effects of the angiotensin converting enzyme inhibitor perindopril on six minute walking distance and quality of life in very old patients with left ventricular systolic dysfunction. Design: Prospective, double blind placebo controlled trial. Setting: Medicine for the elderly day hospital. Patients: 66 patients (average age 81) with left ventricular systolic dysfunction identified by echocardiography. Interventions: 10 weeks of treatment with titrated doses of perindopril or placebo. Main outcome measures: Six minute walking distance 10 weeks following treatment, quality of life measurements including the Minnesota living with heart failure questionnaire and the 36 item short form health survey. Results: In patients with left ventricular systolic dysfunction, six minute walking distance was significantly increased in the treatment group (37.1 m) compared with the placebo group (-0.3 m, p < 0.001). The medication was well tolerated and there were no significant adverse events. Conclusions: Six minute walking distance is improved considerably by treatment with perindopril in older patients with heart failure caused by left ventricular systolic dysfunction. Servier Laboratories Ltd.
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ABSTRACT: Background: Physical function and exercise capacity decline with age and are a major source of disability in older people. Recent evidence suggests a potential role for the renin–angiotensin system in modulating muscle function. We sought to examine the effect of the angiotensin-converting-enzyme (ACE) inhibitor perindopril on physical function in elderly people with functional impairment who had no heart failure or left ventricular systolic dysfunction. Methods: In this double-blind randomized controlled trial, participants aged 65 years and older who had problems with mobility or functional impairment were randomly assigned to receive either perindopril or placebo for 20 weeks. The primary outcome was the change in the 6-minute walking distance over the 20 weeks. Secondary outcomes were changes in muscle function, daily activity levels, self-reported function and health-related quality of life. Results: A total of 130 participants were enrolled in the study (mean age 78.7, standard deviation 7.7 years); 95 completed the trial. At 20 weeks, the mean 6-minute walking distance was significantly improved in the perindopril group relative to the placebo group (mean between-group difference 31.4 m, 95% confidence interval [CI] 10.8 to 51.9 m; p = 0.003). There was a significant impact on health-related quality of life: although the mean score for part 1 of the EQ-5D questionnaire deteriorated over time in the placebo group, quality of life was maintained in the perindopril group, for a between-group difference of 0.09 (p = 0.046). There were no significant differences between the 2 groups in the other outcomes. Interpretation: Use of the ACE inhibitor perindopril improved exercise capacity in functionally impaired elderly people who had no heart failure and maintained health-related quality of life. The degree of improvement was equivalent to that reported after 6 months of exercise training. (International Standard Randomised Controlled Trial Register no. ISRCTN67679521). © 2007 Canadian Medical Association or its licensors Perindopril was supplied free of charge by Servier Laboratories, Slough The study was funded by the Chief Scientist Office, Scottish Executive
