Publications by authors named "Nicholas L M Cruden"

19 Publications

  • Page 1 of 1

Percutaneous Repair of Ventricular Ruptures.

JACC Case Rep 2020 Mar;2(3):341-346

Edinburgh Heart Centre, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom.

Acquired ventricular wall ruptures can be life-threatening. Depending on the pathological features and anatomy, surgical repair can be technically challenging and may be associated with high morbidity and mortality. We present 3 successful percutaneous repairs of different ruptures that used a variety of techniques. ().
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http://dx.doi.org/10.1016/j.jaccas.2019.11.088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083246PMC
March 2020

The challenge of co-existent moderate aortic stenosis and left ventricular systolic impairment.

J Thorac Dis 2017 Oct;9(10):3560-3563

Centre for Cardiovascular Sciences, University of Edinburgh, Edinburgh, UK.

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http://dx.doi.org/10.21037/jtd.2017.09.76DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5723777PMC
October 2017

Endothelial Progenitor Cell Biology and Vascular Recovery Following Transradial Cardiac Catheterization.

J Am Heart Assoc 2017 Oct 28;6(11). Epub 2017 Oct 28.

BHF/University Centre for Cardiovascular Science, University of Edinburgh, United Kingdom.

Background: Transradial catheterization is associated with radial artery injury and vasomotor dysfunction and represents an accessible model of acute vascular injury in humans. We characterized vascular injury and functional recovery to understand the role of circulating endothelial progenitor cells in vascular repair.

Methods And Results: In 50 patients (aged 64±10 years, 70% male) undergoing transradial cardiac catheterization, radial artery injury was assessed by optical coherence tomography and examination of explanted vascular sheaths. Flow- and nitrate-mediated dilatation of the radial artery was assessed in both arms at baseline, at 24 hours, and at 1, 4, and 12 weeks. Circulating endothelial progenitor cell populations were quantified using flow cytometry. Late endothelial outgrowth colonies were isolated and examined in vitro. Optical coherence tomography identified macroscopic injury in 12 of 50 patients (24%), but endothelial cells (1.9±1.2×10 cells) were isolated from all arterial sheaths examined. Compared with the noncatheterized radial artery, flow-mediated vasodilatation was impaired in the catheterized artery at 24 hours (9.9±4.6% versus 4.1±3.1%, <0.0001) and recovered by 12 weeks (8.1±4.9% versus 10.1±4.9%, =0.09). Although the number of CD133 cells increased 24 hours after catheterization (=0.02), the numbers of CD34 cells and endothelial outgrowth colonies were unchanged. Migration of endothelial cells derived from endothelial outgrowth colonies correlated with arterial function before catheterization but was not related to recovery of function following injury.

Conclusions: Transradial cardiac catheterization causes endothelial denudation, vascular injury, and vasomotor dysfunction that recover over 12 weeks. Recovery of vascular function does not appear to be dependent on the mobilization or function of endothelial progenitor cells.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02147119.
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http://dx.doi.org/10.1161/JAHA.117.006610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721759PMC
October 2017

18F-fluoride positron emission tomography for identification of ruptured and high-risk coronary atherosclerotic plaques: a prospective clinical trial.

Lancet 2014 Feb 11;383(9918):705-13. Epub 2013 Nov 11.

Centre for Cardiovascular Science, Clinical Research Imaging Centre, and Division of Pathology, University of Edinburgh, Edinburgh, UK.

Background: The use of non-invasive imaging to identify ruptured or high-risk coronary atherosclerotic plaques would represent a major clinical advance for prevention and treatment of coronary artery disease. We used combined PET and CT to identify ruptured and high-risk atherosclerotic plaques using the radioactive tracers (18)F-sodium fluoride ((18)F-NaF) and (18)F-fluorodeoxyglucose ((18)F-FDG).

Methods: In this prospective clinical trial, patients with myocardial infarction (n=40) and stable angina (n=40) underwent (18)F-NaF and (18)F-FDG PET-CT, and invasive coronary angiography. (18)F-NaF uptake was compared with histology in carotid endarterectomy specimens from patients with symptomatic carotid disease, and with intravascular ultrasound in patients with stable angina. The primary endpoint was the comparison of (18)F-fluoride tissue-to-background ratios of culprit and non-culprit coronary plaques of patients with acute myocardial infarction.

Findings: In 37 (93%) patients with myocardial infarction, the highest coronary (18)F-NaF uptake was seen in the culprit plaque (median maximum tissue-to-background ratio: culprit 1·66 [IQR 1·40-2·25] vs highest non-culprit 1·24 [1·06-1·38], p<0·0001). By contrast, coronary (18)F-FDG uptake was commonly obscured by myocardial uptake and where discernible, there were no differences between culprit and non-culprit plaques (1·71 [1·40-2·13] vs 1·58 [1·28-2·01], p=0·34). Marked (18)F-NaF uptake occurred at the site of all carotid plaque ruptures and was associated with histological evidence of active calcification, macrophage infiltration, apoptosis, and necrosis. 18 (45%) patients with stable angina had plaques with focal (18)F-NaF uptake (maximum tissue-to-background ratio 1·90 [IQR 1·61-2·17]) that were associated with more high-risk features on intravascular ultrasound than those without uptake: positive remodelling (remodelling index 1·12 [1·09-1·19] vs 1·01 [0·94-1·06]; p=0·0004), microcalcification (73% vs 21%, p=0·002), and necrotic core (25% [21-29] vs 18% [14-22], p=0·001).

Interpretation: (18)F-NaF PET-CT is the first non-invasive imaging method to identify and localise ruptured and high-risk coronary plaque. Future studies are needed to establish whether this method can improve the management and treatment of patients with coronary artery disease.

Funding: Chief Scientist Office Scotland and British Heart Foundation.
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http://dx.doi.org/10.1016/S0140-6736(13)61754-7DOI Listing
February 2014

Vasomotor and fibrinolytic responses to kinin receptor agonists in the atherosclerotic human lower limb.

Heart Vessels 2012 Mar 11;27(2):179-85. Epub 2011 Mar 11.

Centre for Cardiovascular Science, University of Edinburgh, Room F2339, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 5SB, UK.

Upregulation of vascular B(1) kinin receptor expression has been reported in human atheroma, but its role remains unclear. We examined vasomotor and fibrinolytic responses to selective B(1) and B(2) kinin receptor agonism in the human femoral circulation and correlated responses with femoral arterial plaque load. Femoral arterial cross-sectional area, blood flow and plaque volume were determined using intravascular ultrasound and Doppler during selective arterial infusion of Lys-des-Arg(9)-bradykinin (B(1) agonist), bradykinin (B(2) agonist) and sodium nitroprusside in eleven patients undergoing diagnostic coronary angiography. Net release of tissue plasminogen activator was determined across the femoral vascular bed. Mean femoral arterial plaque load was 8.1 (±0.9) mm(3)/mm of vessel. Bradykinin and sodium nitroprusside caused dose-dependent increases in femoral blood flow (p < 0.05 and p < 0.005, respectively). Bradykinin caused a dose-dependent increase in net tissue plasminogen activator release (p < 0.05), which was augmented by angiotensin-converting enzyme inhibition (p < 0.05). There were no correlations between plaque load and bradykinin-mediated vasodilation or tissue plasminogen activator release. Lys-des-Arg(9)-bradykinin had no effect on blood flow or tissue plasminogen activator release. The vasomotor and fibrinolytic actions of bradykinin in the femoral circulation are mediated solely by the B(2) kinin receptor, irrespective of the presence of atheroma. In keeping with previous data, bradykinin-mediated tissue plasminogen activator release was augmented in the presence of angiotensin-converting enzyme inhibition consistent with its putative vascular protective effect.
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http://dx.doi.org/10.1007/s00380-011-0124-6DOI Listing
March 2012

Clopidogrel loading dose and bleeding outcomes in patients undergoing urgent coronary artery bypass grafting.

Am Heart J 2011 Feb;161(2):404-10

Victoria Heart Institute Foundation, Victoria, British Columbia, Canada.

Background: Coronary artery bypass grafting (CABG) performed within 5 days of clopidogrel administration is associated with increased bleeding. The impact of clopidogrel loading dose is unknown. We examined the effect of clopidogrel loading dose on bleeding outcomes in patients undergoing urgent CABG.

Methods: Clinical outcomes were examined retrospectively for 196 consecutive patients undergoing urgent CABG within 5 days of a clopidogrel loading dose between January 2003 and June 2009. Major bleeding was defined as a fall in hemoglobin > 5 g/dL, fatal or intracranial bleeding, or cardiac tamponade.

Results: One hundred forty-eight patients received 300 mg and 48 patients received ≥ 600 mg clopidogrel loading. Patients were predominantly male (78%) with a mean age of 66 ± 10 years. Mean duration from clopidogrel loading to CABG was 3.0 ± 1.5 and 3.0 ± 1.6 days for the 300 and 600 mg loading doses, respectively. Major bleeding occurred in 47% of patients receiving 300 mg and 73% of patients receiving ≥ 600 mg clopidogrel loading (P = .002). Compared with 300 mg, patients receiving ≥ 600 mg had greater 24-hour chest tube output (391 ± 251 vs 536 ± 354 mL, P = .01), stayed longer in surgical intensive care (4.3 ± 4.1 vs 5.0 ± 3.1 days, P = .0001), and trended toward greater reoperation for bleeding (5% vs 12%, P = .09). Following multivariate analysis, clopidogrel loading dose ≥ 600 mg (odds ratio 2.8, CI 1.2-6.6), preoperative hemoglobin (3.4, 2.7-5.0 per 1 g/dL increase), and female gender (2.9, 1.1-7.4) predicted major bleeding.

Conclusions: Higher clopidogrel loading doses are associated with increased bleeding when administered within 5 days of CABG. The development of shorter-acting, reversible, oral antiplatelet agents may reduce perioperative bleeding in this population.
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http://dx.doi.org/10.1016/j.ahj.2010.10.037DOI Listing
February 2011

Previous coronary stent implantation and cardiac events in patients undergoing noncardiac surgery.

Circ Cardiovasc Interv 2010 Jun 4;3(3):236-42. Epub 2010 May 4.

Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.

Background: Noncardiac surgery performed after coronary stent implantation is associated with an increased risk of stent thrombosis, myocardial infarction, and death. The influence of stent type and period of risk still have to be defined.

Methods And Results: We linked the Scottish Coronary Revascularisation Register with hospital admission data to undertake a Scotland-wide retrospective cohort study examining cardiac outcomes in all patients who received drug-eluting or bare-metal stents between April 2003 and March 2007 and subsequently underwent noncardiac surgery. Of 1953 patients, 570 (29%) were treated with at least 1 drug-eluting stent and 1383 (71%) with bare-metal stents only. There were no differences between drug-eluting and bare-metal stents in the primary end point of in-hospital mortality or ischemic cardiac events (14.6% versus 13.3%; P=0.3) or the secondary end points of in-hospital mortality (0.7% versus 0.6%; P=0.8) and acute myocardial infarction (1.2% versus 0.7%; P=0.3). Perioperative death and ischemic cardiac events occurred more frequently when surgery was performed within 42 days of stent implantation (42.4% versus 12.8% beyond 42 days; P<0.001), especially in patients revascularized after an acute coronary syndrome (65% versus 32%; P=0.037). There were no temporal differences in outcomes between the drug-eluting and bare-metal stent groups.

Conclusions: Patients undergoing noncardiac surgery after recent coronary stent implantation are at increased risk of perioperative myocardial ischemia, myocardial infarction, and death, particularly after an acute coronary syndrome. For at least 2 years after percutaneous coronary intervention, cardiac outcomes after noncardiac surgery are similar for both drug-eluting and bare-metal stents.
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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.109.934703DOI Listing
June 2010

Coronary stent thrombosis in the perioperative period.

BMJ 2008 Nov 24;337:a2074. Epub 2008 Nov 24.

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http://dx.doi.org/10.1136/bmj.a2074DOI Listing
November 2008

Therapeutic potential of icatibant (HOE-140, JE-049).

Expert Opin Pharmacother 2008 Sep;9(13):2383-90

University of Edinburgh, Centre for Cardiovascular Science, Chancellor's Building, 49 Little France Crescent, Little France, Edinburgh EH164SB, UK.

There is now a substantial body of work implicating bradykinin, an endogenous peptide neurohormone, in the pathophysiology of a variety of inflammatory conditions in man. Icatibant (HOE-140, JE-049), a highly selective antagonist at the bradykinin B2 receptor, blocks the vasodilatation and increased vascular permeability associated with exogenous bradykinin administration both in experimental models and in vivo in man. Recent attention has focused on the therapeutic potential of icatibant in a number of human disease states. The most promising of these is hereditary angioedema in which Phase III clinical trials have recently been completed and regulatory approval is currently being sought in Europe and the USA. A therapeutic role for icatibant has also been proposed in several other human conditions including drug-induced angioedema, airways disease, thermal injury, refractory ascites in patients with liver cirrhosis, and acute pancreatitis, although this work remains largely experimental.
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http://dx.doi.org/10.1517/14656566.9.13.2383DOI Listing
September 2008

Isolated left ventricular non-compaction as an unusual cause of heart failure: a case report.

J Med Case Rep 2008 Aug 13;2:269. Epub 2008 Aug 13.

Department of Cardiology, Royal Infirmary of Edinburgh, Little France Crescent, Little France, Edinburgh, UK.

Introduction: Isolated left ventricular non-compaction is a recently described form of cardiomyopathy that is associated with a significant risk of life-threatening arrhythmia and thromboembolic complications.

Case Presentation: We report the presentation, diagnosis and management of isolated left ventricular non-compaction in a 54-year-old Caucasian woman presenting with progressive symptoms of heart failure.

Conclusion: Advances in diagnostic imaging have undoubtedly led to an increase in the detection of isolated left ventricular non-compaction. Diagnosing and differentiating this uncommon condition from other forms of cardiomyopathy are important as treatment and prognosis may differ significantly. Our current understanding of isolated left ventricular non-compaction, including diagnostic criteria, management and prognosis, is discussed.
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http://dx.doi.org/10.1186/1752-1947-2-269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2527577PMC
August 2008

Reduced vascular complications and length of stay with transradial rescue angioplasty for acute myocardial infarction.

Catheter Cardiovasc Interv 2007 Nov;70(5):670-5

Centre for Cardiovascular Science, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom.

Objectives: The aim of this study was to compare clinical outcomes for transradial and transfemoral percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction undergoing rescue angioplasty.

Background: Transfemoral percutaneous coronary intervention in patients with acute myocardial infarction treated with systemic thrombolysis is associated with a significant risk of vascular complications. A transradial approach may reduce vascular complications, improve mobilization and facilitate earlier discharge.

Methods: In a retrospective analysis, clinical outcomes for 287 consecutive patients undergoing rescue angioplasty for acute myocardial infarction were determined. Data were recorded using a standardized proforma and analyzed using SPSS.

Results: Procedural success was similar for the transradial and transfemoral routes (98% vs. 93%; P = 0.3). There was a reduction in vascular complications (0 (0%) vs. 32 (13%); P < 0.01) and post-procedural length of stay (7.0 +/- 7.9 vs. 7.9 +/- 5.6 days; P < 0.005) in the radial group when compared with the femoral group. There were no differences in procedural or in-hospital mortality, procedure duration, or radiation dose between the two groups.

Conclusion: Rescue angioplasty performed via the radial artery is safe, effective, and associated with a reduction in vascular complications and length of hospital stay when compared with the femoral approach. These findings suggest that where facilities and experience allow rescue angioplasty in patients with acute myocardial infarction should be performed via the radial artery.
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http://dx.doi.org/10.1002/ccd.21182DOI Listing
November 2007

Saphenous vein graft aneurysm.

Eur Heart J 2007 May 6;28(9):1071. Epub 2006 Nov 6.

Department of Cardiology, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.

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http://dx.doi.org/10.1093/eurheartj/ehl370DOI Listing
May 2007

Plasma TAFI and soluble CD40 ligand do not predict reperfusion following thrombolysis for acute myocardial infarction.

Thromb Res 2006 1;118(2):189-97. Epub 2005 Aug 1.

Centre for Cardiovascular Science, University of Edinburgh, Royal Infirmary of Edinburgh, UK.

Introduction: Thrombolytic therapy fails to achieve reperfusion in almost a third of patients with acute myocardial infarction. Thrombin activatable fibrinolysis inhibitor (TAFI) and soluble CD40 ligand (sCD40L) are novel endogenous fibrinolytic and atherothrombotic factors that determine clot stability. We investigated whether admission plasma thrombin activatable fibrinolysis inhibitor (TAFI) and soluble CD40 ligand (sCD40L) concentrations predicted reperfusion following thrombolytic therapy in patients with acute myocardial infarction.

Materials And Methods: Prior to administration of thrombolytic therapy, venous blood was collected from 110 patients presenting with acute ST segment elevation myocardial infarction and plasma assayed for tissue plasminogen activator (t-PA) antigen and activity, plasminogen activator inhibitor type-1 antigen (PAI-1), TAFI antigen and activity, C-reactive protein (CRP) and sCD40L concentrations. Reperfusion was determined using continuous ST segment monitoring.

Results: Reperfusion occurred in 77 (70%) patients with a mean treatment to reperfusion time of 83 +/- 46 min. Peak creatine kinase was significantly lower in patients who reperfused (1578 +/- 1199 versus 2200 +/- 1744 U/L; P < 0.05) and correlated with time to reperfusion (r = 0.44 [95% CI: 0.23 - 0.61], P = 0.0001). There was a modest correlation between plasma TAFI antigen and activity (r = 0.3 [95% CI: 0.04 - 0.53]; P < 0.05). There were no significant associations between coronary reperfusion and plasma concentrations of t-PA, PAI-1, TAFI, CRP or sCD40L.

Conclusions: Systemic plasma TAFI, sCD40L and CRP concentrations do not predict reperfusion in patients receiving thrombolytic therapy for acute ST elevation myocardial infarction.
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http://dx.doi.org/10.1016/j.thromres.2005.06.014DOI Listing
August 2006

Clots, kinins and coronaries.

Atherosclerosis 2005 Dec 14;183(2):189-98. Epub 2005 Jul 14.

Department of Cardiology, Royal Infirmary of Edinburgh, Little France, Edinburgh EH16 5SA, UK. nick

The dynamic regulation of intravascular thrombus formation is central to our understanding of both acute and chronic atherosclerotic events. The initiation, modification and resolution of thrombus associated with eroded or unstable coronary plaques is critically dependent on the efficacy of endogenous fibrinolysis, a process that is itself reliant upon the cellular activation and function of the surrounding endothelium and vascular wall. Bradykinin is a vasodilator peptide that stimulates the endothelium to release the pro-lytic factor, tissue-type plasminogen activator and is released at sites of intravascular thrombus formation including the luminal surface of ruptured or eroded atheromatous plaques. Recent studies have provided important and novel insights into the contribution of bradykinin to the regulation of endogenous fibrinolysis and intravascular thrombosis in the peripheral and coronary circulations in vivo in man. Moreover, the pro-fibrinolytic effects of bradykinin are markedly augmented in the presence of angiotensin-converting enzyme inhibition and may explain, at least in part, the established anti-ischaemic effects of angiotensin-converting enzyme inhibitors in patients with atherosclerosis. The development of novel agents that potentiate bradykinin and endogenous fibrinolysis, such as inhibitors of thrombin activatable fibrinolysis inhibitor, may provide future therapeutic strategies to treat and prevent cardiovascular disease.
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http://dx.doi.org/10.1016/j.atherosclerosis.2005.05.038DOI Listing
December 2005

B1 kinin receptor does not contribute to vascular tone or tissue plasminogen activator release in the peripheral circulation of patients with heart failure.

Arterioscler Thromb Vasc Biol 2005 Apr 27;25(4):772-7. Epub 2005 Jan 27.

Centre for Cardiovascular Science, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom, EH16 4SB.

Objective: Vascular expression of the B1 kinin receptor is markedly upregulated with left ventricular dysfunction and angiotensin-converting enzyme (ACE) inhibition, but its function remains unclear. Inhibitors of ACE potentiate bradykinin-mediated B2 receptor-dependent vasodilatation and tissue plasminogen activator (tissue-type plasminogen activator [t-PA]) release. We investigated the contribution of the B1 receptor to the maintenance of vascular tone and t-PA release in patients with heart failure.

Methods And Results: Eleven patients were treated with enalapril (10 mg twice daily) or losartan (50 mg twice daily) in a randomized double-blind crossover trial. During week 6 of each treatment, patients received an intrabrachial infusion of Lys-des-Arg9-bradykinin (B1 agonist; 1 to 10 nmol/min), bradykinin (30 to 300 pmol/min), Lys-[Leu8]-des-Arg9-bradykinin (B1 antagonist; 1 to 10 nmol/min), and norepinephrine (60 to 540 pmol/min). Blood flow and t-PA release were measured using venous occlusion plethysmography and blood sampling. Bradykinin (P<0.001 for all), but not Lys-des-Arg9-bradykinin, caused vasodilatation and t-PA antigen and activity release. Norepinephrine (P<0.001), but not Lys-[Leu8]-des-Arg9-bradykinin, caused vasoconstriction. Compared with losartan, enalapril augmented bradykinin-mediated vasodilatation (P<0.05) and t-PA release (P<0.01 for all) but had no effect on B(1) receptor-mediated responses.

Conclusions: The B1 kinin receptor does not have a major vasomotor or fibrinolytic role in patients with heart failure. Augmentation of kinin-mediated vasodilatation and t-PA release by ACE inhibition is restricted to the B2 receptor.
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http://dx.doi.org/10.1161/01.ATV.0000157157.78822.25DOI Listing
April 2005

Angiotensin antagonism in patients with heart failure: ACE inhibitors, angiotensin receptor antagonists or both?

Am J Cardiovasc Drugs 2004 ;4(6):345-53

Department of Cardiology, Cardiovascular Research, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, UK.

Chronic heart failure (CHF) is a major cause of morbidity and mortality in western society. It is now widely accepted that the renin-angiotensin-aldosterone system (RAAS) and, in particular, angiotensin II (A-II) play a key role in the pathophysiology of CHF. Large-scale clinical trials have demonstrated that inhibitors of angiotensin-converting enzyme (ACE), the principal enzyme responsible for A-II production, improve symptoms and survival in patients with CHF. This enzyme is also responsible for the breakdown of the vasodilator hormone bradykinin. Administration of ACE inhibitors is associated with increased plasma bradykinin levels and this is thought to contribute to the vascular changes associated with ACE inhibitor therapy. However, RAAS inhibition with ACE inhibitors remains incomplete because ACE inhibitors do not block the non-ACE-mediated conversion of angiotensin I to A-II. Angiotensin receptor antagonists (angiotensin receptor blockers; ARBs) antagonize the action of A-II at the A-II type 1 (AT(1)) receptor, whilst allowing the potentially beneficial actions of A-II mediated via the A-II type 2 (AT(2)) receptor. Evidence that the clinical benefit demonstrated with ACE inhibitors in patients with CHF may extend to ARBs has only emerged recently. Combination therapy with both an ACE inhibitor and an ARB has a number of potential advantages and has been investigated in several large-scale clinical trials recently. In patients with CHF, first-line therapy should include an ACE inhibitor and a beta-adrenoceptor antagonist. The addition of an ARB provides symptomatic relief but has not been shown to improve survival. Where an ACE inhibitor is not tolerated, treatment with an ARB would seem an appropriate alternative. There is insufficient data to support the routine use of ARBs as first-line therapy in the management of CHF.
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http://dx.doi.org/10.2165/00129784-200404060-00002DOI Listing
March 2005

Neutral endopeptidase inhibition augments vascular actions of bradykinin in patients treated with angiotensin-converting enzyme inhibition.

Hypertension 2004 Dec 18;44(6):913-8. Epub 2004 Oct 18.

Centre for Cardiovascular Science, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom, EH16 4SB.

Angiotensin-converting enzyme and neutral endopeptidase (EC 3.4.24.11; neprilysin) are metallopeptidases present on the endothelium that metabolize bradykinin. Inhibitors of angiotensin-converting enzyme potentiate bradykinin-mediated vasodilatation and endothelial tissue plasminogen activator release. Combined angiotensin-converting enzyme and neutral endopeptidase inhibition may have additional beneficial cardiovascular effects mediated through bradykinin potentiation. We investigated the effects of local neutral endopeptidase inhibition on the vascular actions of bradykinin in heart failure patients maintained on chronic angiotensin-converting enzyme inhibition. Ten patients received intrabrachial infusion of thiorphan (30 nmol/min), a neutral endopeptidase inhibitor, in a randomized double-blind placebo-controlled crossover trial. Thiorphan was coinfused with Lys-des-Arg9-bradykinin (1 to 10 nmol/min), bradykinin (30 to 300 pmol/min), atrial natriuretic peptide (10 to 100 pmol/min), and sodium nitroprusside (2 to 8 mug/min). Bradykinin, atrial natriuretic peptide, and sodium nitroprusside caused dose-dependent vasodilatation (peak blood flow 14.4+/-2.2, 3.6+/-0.6, and 8.6+/-1.3 mL per 100 mL/min, respectively; P<0.0001). Bradykinin caused dose-dependent increases in tissue plasminogen activator antigen and activity (peak concentration 31.8+/-3.4 ng/mL and 21.9+/-7.6 IU/mL, respectively; P<0.001) and estimated antigen and activity release (peak release 152+/-46 ng per 100 mL/min and 154+/-22 IU/100 mL/min, respectively; P<0.005). Compared with placebo, thiorphan augmented bradykinin-mediated vasodilatation (1.4-fold; P<0.0001) and net tissue plasminogen activator release (1.5-fold; P<0.005). Neutral endopeptidase contributes to bradykinin metabolism in heart failure patients maintained on angiotensin-converting enzyme inhibitor therapy. Our findings may explain some of the clinical effects of combined angiotensin-converting enzyme and neutral endopeptidase inhibition, including the greater vasodepressor effect observed with combined therapy when compared with angiotensin-converting enzyme inhibition alone.
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http://dx.doi.org/10.1161/01.HYP.0000146483.78994.56DOI Listing
December 2004

Bradykinin contributes to the systemic hemodynamic effects of chronic angiotensin-converting enzyme inhibition in patients with heart failure.

Arterioscler Thromb Vasc Biol 2004 Jun 22;24(6):1043-8. Epub 2004 Apr 22.

Centre for Cardiovascular Science, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom EH16 4SB.

Background: Bradykinin is an endogenous vasodilator that may contribute to the systemic effects of angiotensin-converting enzyme (ACE) inhibitor therapy. Using B9340, a bradykinin receptor antagonist, we determined the contribution of bradykinin to the systemic hemodynamic effects of long-term ACE inhibition in patients with chronic heart failure.

Methods And Results: Fourteen patients with heart failure received enalapril (10 mg twice daily) or losartan (50 mg twice daily) in a randomized double-blind crossover trial. After 6 weeks treatment, patients underwent right heart catheterization and were randomized to an intravenous infusion of B9340 (2 to 20 microg/kg per minute) or saline placebo. After B9340 infusion in patients treated with enalapril, mean arterial pressure (+5.2 mm Hg), systemic vascular resistance (+315 dynes x s/cm5), pulmonary arterial wedge pressure (-1.4 mm Hg), and mean pulmonary arterial pressure (-1.3 mm Hg) were greater compared with losartan (P<0.005, P=0.07, P<0.0001, and P<0.05 respectively) or placebo infusion (P< or =0.005 for all). There was a reduction in cardiac output after B9340 with enalapril compared with placebo (P<0.001) but not losartan.

Conclusions: Bradykinin contributes to the systemic hemodynamic effects of long-term ACE inhibition in patients with heart failure. This mechanism may explain the apparent clinical differences between ACE inhibitors and angiotensin receptor blockers in the treatment of heart failure.
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http://dx.doi.org/10.1161/01.ATV.0000129331.21092.1dDOI Listing
June 2004

Salmeterol for the prevention of high-altitude pulmonary edema.

N Engl J Med 2002 Oct;347(16):1282-5; author reply 1282-5

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http://dx.doi.org/10.1056/NEJM200210173471618DOI Listing
October 2002