David E. Newby

Intra-Arterial Tumor Necrosis Factor-α Impairs Endothelium-Dependent Vasodilatation and Stimulates Local Tissue Plasminogen Activator Release in Humans

Objective—Inflammation contributes to the pathogenesis of cardiovascular disease, potentially through the actions of proinflammatory cytokines. We assessed the direct effects of local intra-arterial tumor necrosis factor-&agr; (TNF-&agr;), interleukin-6, and endotoxin on blood flow and endogenous tissue plasminogen activator (t-PA) release in vivo in humans. Methods and Results—In a double-blind, randomized, placebo-controlled trial, blood flow, plasma cytokine, and fibrinolytic parameters were measured using venous occlusion plethysmography and blood sampling. Ten subjects received intrabrachial TNF-&agr;, interleukin-6, and endotoxin infusions, and 8 additional subjects received intrabrachial infusions of bradykinin, acetylcholine, and sodium nitroprusside after pretreatment with TNF-&agr;. TNF-&agr; but not interleukin-6, endotoxin, or placebo caused a gradual and sustained ≈20-fold increase in plasma t-PA concentrations (P <0.001) that was associated with elevated plasma interleukin-6 concentrations (P <0.05) but without an effect on blood flow or plasminogen activator inhibitor type 1 antigen. Compared with placebo, TNF-&agr; pretreatment impaired bradykinin- and acetylcholine-induced vasodilatation (P <0.03) and resulted in a doubling of bradykinin-induced t-PA release (P <0.05). Conclusions—Intra-arterial TNF-&agr; causes an acute local vascular inflammation that is associated with impaired endothelium-dependent vasomotion as well as a sustained and substantial increase in endothelial t-PA release. TNF-&agr; has potentially both adverse vasomotor and beneficial profibrinolytic effects on endothelial function.

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

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.

The l-arginine/nitric oxide pathway contributes to the acute release of tissue plasminogen activator in vivo in man

Objective : Effective endogenous fibrinolysis requires rapid release of endothelial tissue plasminogen activator (t-PA). Using the nitric oxide synthase inhibitor, l- N G-monomethylarginine (l-NMMA), we examined the contribution of endogenous nitric oxide to substance P-induced t-PA release in vivo in man. Methods : Blood flow and plasma fibrinolytic and haemostatic factors were measured in both forearms of 8 healthy male volunteers who received unilateral brachial artery infusions of substance P (2–8 pmol/min) and l-NMMA (1–4 μg/min). Results : Substance P caused dose-dependent increases in blood flow ( P <0.001) and plasma t-PA antigen ( P =0.04) and activity ( P <0.001) concentrations confined to the infused forearm, but had no effect on plasminogen activator inhibitor type 1 (PAI-1) or von Willebrand factor concentrations. In the presence of l-NMMA, substance P again caused significant increases in blood flow ( P <0.001) and t-PA antigen ( P =0.003) and activity ( P <0.001) concentrations but these increases were significantly less than with substance P alone ( P <0.001, P =0.05 and P <0.01, respectively). l-NMMA alone significantly reduced blood flow in the infused arm, but had no measurable effect on t-PA or PAI-1 concentrations. Conclusions : The l-arginine/nitric oxide pathway contributes to substance P-induced t-PA release in vivo in man. This provides an important potential mechanism whereby endothelial dysfunction increases the risk of atherothrombosis through a reduction in the acute fibrinolytic capacity.

Marked bradykinin-induced tissue plasminogen activator release in patients with heart failure maintained on long-term angiotensin-converting enzyme inhibitor therapy☆

OBJECTIVESnThe aim of the present study was to assess the contribution of angiotensin-converting enzyme (ACE) inhibitor therapy to bradykinin-induced tissue-type plasminogen activator (t-PA) release in patients with heart failure (HF) secondary to ischemic heart disease.nnnBACKGROUNDnBradykinin is a potent endothelial cell stimulant that causes vasodilatation and t-PA release. In large-scale clinical trials, ACE inhibitor therapy prevents ischemic events.nnnMETHODSnNine patients with symptomatic HF were evaluated on two occasions: during and following seven-day withdrawal of long-term ACE inhibitor therapy. Forearm blood flow was measured using bilateral venous occlusion plethysmography. Intrabrachial bradykinin (30 to 300 pmol/min), substance P (2 to 8 pmol/min), and sodium nitroprusside (1 to 4 pmol/min) were infused, and venous blood samples were withdrawn from both forearms for estimation of fibrinolytic variables.nnnRESULTSnOn both study days, bradykinin and substance P caused dose-dependent vasodilatation and release of t-PA from the infused forearm (p < 0.05 by analysis of variance [ANOVA]). Long-term ACE inhibitor therapy caused an increase in forearm vasodilatation (p < 0.05 by ANOVA) and t-PA release (p < 0.001 by ANOVA) during bradykinin, but not substance P, infusion. Maximal local plasma t-PA activity concentrations approached 100 IU/ml, and maximal forearm protein release was approximately 4.5 microg/min.nnnCONCLUSIONSnLong-term ACE inhibitor therapy augments bradykinin-induced peripheral vasodilatation and local t-PA release in patients with HF due to ischemic heart disease. Local plasma t-PA activity concentrations approached those seen during systemic thrombolytic therapy for acute myocardial infarction. This may contribute to the primary mechanism of the anti-ischemic effects associated with long-term ACE inhibitor therapy.

Peripheral vascular tone in patients with cirrhosis: role of the renin–angiotensin and sympathetic nervous systems

OBJECTIVEnThe aims of the study were to establish the roles of angiotensin II and of the cardiopulmonary baroreceptor reflex in the regulation of peripheral vascular tone in patients with cirrhosis.nnnMETHODSnForearm blood flow responses to subsystemic, locally active intrabrachial infusions were measured in patients with Childs Grade C cirrhosis and matched controls using bilateral venous occlusion plethysmography. Responses were determined to the angiotensin II type I receptor antagonist, losartan, noradrenaline, angiotensin II and the nitric oxide synthase inhibitor, L-NG-monomethyl arginine.nnnRESULTSnLosartan at 30 and 90 micrograms/min caused no significant change in blood flow in controls, but caused 23 +/- 6% and 27 +/- 5% increases in patients respectively (p < 0.001). Lower body negative pressure caused a mean bilateral reduction in forearm blood flow of 20 +/- 4% in controls (p < 0.001) but only tended to reduce flow (9 +/- 5%; p = 0.06) in patients (p < 0.001; controls vs. patients). Noradrenaline, angiotensin II and L-NG-monomethyl arginine caused significant vasoconstriction (p < 0.001) in both patients and controls although angiotensin II caused significantly less vasoconstriction in patients (p = 0.01).nnnCONCLUSIONSnWe conclude that angiotensin II makes an important contribution to basal peripheral vascular tone in patients with cirrhosis in the face of reduced vascular responses to its local administration. In addition, the vasoconstrictor response to cardiopulmonary baroreceptor unloading is attenuated despite normal vascular responses to noradrenaline. These responses are consistent with chronic activation of the renin-angiotensin and sympathetic nervous systems in patients with advanced cirrhosis.

Vascular and fibrinolytic effects of intra-arterial tumour necrosis factor-α in patients with coronary heart disease

Elevated plasma t-PA (tissue plasminogen activator) and serum CRP (C-reactive protein) concentrations are associated with an adverse cardiovascular risk. In the present study, we investigated whether acute local inflammation causes vascular dysfunction and influences t-PA release in patients with stable coronary heart disease. Serum CRP, plasma t-PA and PAI-1 (plasminogen activator inhibitor type 1) concentrations were determined in 95 patients with stable coronary heart disease. A representative subpopulation of 12 male patients received an intra-brachial infusion of TNF-alpha (tumour necrosis factor-alpha) and saline placebo using a randomized double-blind cross-over study design. Forearm blood flow and plasma fibrinolytic and inflammatory variables were measured. Serum CRP concentrations correlated with plasma t-PA concentrations (r=0.37, P<0.001) and t-PA/PAI-1 ratio (r=-0.21, P<0.05). Intra-arterial TNF-alpha caused a rise in t-PA concentrations (P<0.001) without affecting blood flow or PAI-1 concentrations. TNF-alpha pretreatment impaired acetylcholine- and sodium nitroprusside-induced vasodilatation (P<0.001 for both) whilst doubling bradykinin-induced t-PA release (P=0.006). In patients with stable coronary heart disease, plasma fibrinolytic factors correlate with a systemic inflammatory marker and local vascular inflammation directly impairs vasomotor function whilst enhancing endothelial t-PA release. We suggest that the adverse prognosis associated with elevated plasma t-PA concentrations relates to the underlying causative association with vascular inflammation and injury.

Acute systemic inflammation enhances endothelium-dependent tissue plasminogen activator release in men ☆

OBJECTIVESnThe purpose of this study was to investigate in vivo the effects of acute systemic inflammation on the endogenous fibrinolytic capacity in men.nnnBACKGROUNDnSystemic inflammation and endogenous fibrinolysis play a major role in the pathogenesis of coronary artery disease. Although previous studies have shown impaired endothelium-dependent vasomotor function, the effects of inflammation on the endothelial release of the fibrinolytic factor tissue plasminogen activator (t-PA) are unknown.nnnMETHODSnIn a double-blind randomized placebo-controlled crossover trial, we administered a mild inflammatory stimulus, Salmonella typhi vaccine, or saline placebo to eight healthy men on two separate occasions. Six hours after vaccination, blood flow and plasma fibrinolytic variables were measured in both arms during intrabrachial infusions of bradykinin (40 to 1,000 pmol/min), acetylcholine (5 to 20 microg/min), and sodium nitroprusside (2 to 8 microg/min).nnnRESULTSnCompared with placebo, the S. typhi vaccination caused a rise in white cell count (11.1 +/- 0.5 x10(9)/l vs. 7.9 +/- 0.8 x10(9)/l; p = 0.004) and plasma interleukin-6 concentrations (6.9 +/- 1.4 pg/ml vs. 1.6 +/- 0.4 pg/ml; p = 0.01) in addition to a significant augmentation of t-PA antigen (45 +/- 9 ng/100 ml/min at peak dose vs. 24 +/- 8 ng/100 ml/min at peak dose; p = 0.016, analysis of variance) and activity (104 +/- 15 IU/100 ml/min vs. 54 +/- 12 IU/100 ml/min; p = 0.006, analysis of variance) release during bradykinin infusion. Forearm blood flow increased in a dose-dependent manner after bradykinin, acetylcholine and sodium nitroprusside infusions (p < 0.001), but this was unaffected by vaccination.nnnCONCLUSIONSnOur results showed that acute systemic inflammation augmented local forearm t-PA release in men, which suggests that acute inflammation may invoke a protective response by enhancing the acute endogenous fibrinolytic capacity in healthy men. Further studies are needed to clarify whether this response is impaired in patients with cardiovascular disease.

A single-particle characterization of a mobile Versatile Aerosol Concentration Enrichment System for exposure studies

BackgroundAn Aerosol Time-of-Flight Mass Spectrometer (ATOFMS) was used to investigate the size and chemical composition of fine concentrated ambient particles (CAPs) in the size range 0.2–2.6 μm produced by a Versatile Aerosol Concentration Enrichment System (VACES) contained within the Mobile Ambient Particle Concentrator Exposure Laboratory (MAPCEL). The data were collected during a study of human exposure to CAPs, in Edinburgh (UK), in February-March 2004. The air flow prior to, and post, concentration in the VACES was sampled in turn into the ATOFMS, which provides simultaneous size and positive and negative mass spectral data on individual fine particles.ResultsThe particle size distribution was unaltered by the concentrator over the size range 0.2–2.6 μm, with an average enrichment factor during this study of ~5 (after dilution of the final air stream). The mass spectra from single particles were objectively grouped into 20 clusters using the multivariate K-means algorithm and then further grouped manually, according to similarity in composition and time sequence, into 8 main clusters. The particle ensemble was dominated by pure and reacted sea salt and other coarse inorganic dusts (as a consequence of the prevailing maritime-source climatology during the study), with relatively minor contributions from carbonaceous and secondary material. Very minor variations in particle composition were noted pre- and post-particle concentration, but overall there was no evidence of any significant change in particle composition.ConclusionThese results confirm, via single particle analysis, the preservation of the size distribution and chemical composition of fine ambient PM in the size range 0.2–2.6 μm after passage through the VACES concentration instrumentation.

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

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 (AT1) receptor, whilst allowing the potentially beneficial actions of A-II mediated via the A-II type 2 (AT2) 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 β-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.

Health utility and survival after hospital admission with acute cardiogenic pulmonary oedema

Background The aim of this study was to measure health utility and survival in patients with acute cardiogenic pulmonary oedema (ACPO), identify predictors of outcome and determine the effect of initial treatment with non-invasive ventilation (NIV) upon outcomes. Methods A randomised controlled trial was conducted at 26 hospitals in the UK. 1069 adults with ACPO were randomised to continuous positive airway pressure (CPAP), non-invasive positive pressure ventilation (NIPPV) or standard oxygen therapy. The main outcome measures were survival to 1–5u2005years, health utility measured using the EQ-5D survey at 1, 3 and 6u2005months, and quality-adjusted life years (QALYs). Results Median survival was 771u2005days (95% CI 669 to 875), with no difference between the three treatment groups (p=0.827). Age (HR 1.042, 95% CI 1.031 to 1.052), chronic obstructive pulmonary disease (HR 1.13, 95% CI 1.06 to 1.62), cerebrovascular disease (HR 1.41, 95% CI 1.14 to 1.73) and diabetes mellitus (HR 1.31, 95% CI 1.01 to 1.63) independently predicted mortality. Mean EQ-5D scores were 0.578, 0.576 and 0.582 at 1, 3 and 6u2005months, respectively, with no significant difference between the treatment groups. Male gender (+0.045 QALYs, 95% CI 0.009 to 0.081) and cerebrovascular disease (−0.080 QALYs, 95% CI −0.131 to −0.029) independently predicted health utility. Conclusion Patients with ACPO have high mortality and reduced health utility. Initial treatment with CPAP or NIPPV does not alter subsequent survival or health utility.