Bradykinin: vasomotor tone and endogenous fibrinolysis in man

Bradykinin is a nonapetide released into plasma during the contact phase of blood coagulation. It has a wide variety of physiological effects including vasodilatation, tissue-type plasminogen activator (t-PA) release, inflammatory mediator, ischaemic preconditioning and vasculogenesis. It is inactivated in plasma by angiotensinconverting enzyme (ACE). Inhibition of this enzyme has been shown to be beneficial in a variety of cardiovascular disorders including heart failure and hypertension, and it is clear that this benefit is not due entirely to reduction in the bioavailability of angiotensin II. We hypothesised that• bradykinin is a vasodilator and stimulates endothelial t-PA release via a specific receptor and that this effect is augmented by ACE inhibition• in patients with heart failure, bradykinin contributes to peripheral and systemic vascular tone during treatment with ACE inhibition.Forearm blood flow was measured using bilateral forearm plethysmography during intrabrachial drug infusion. Bilateral venous cannulae were inserted to perform blood sampling for estimation of plasma t-PA and plasminogen activator inhibitor 1 (PAI1) concentrations. Cardiac output was measured with pulmonary artery catheterisation. The novel peptide bradykinin receptor antagonist, B9340, was used to oppose the effects of bradykinin.Studies were performed in healthy volunteers• to demonstrate the pharmacodynamics of B9340 and to demonstrate the selectivity of B9340 in opposing bradykinin-induced t-PA release.• to demonstrate the safety and tolerability of systemic intravenous B9340 administration.Studies were performed in patients with heart failure• to demonstrate the effect of ACE inhibition on endothelial t-PA release.• to demonstrate the effect of bradykinin antagonism on peripheral and systemic vascular tone in patients treated with ACE inhibition and angiotensin receptor blockade.RESULTS In healthy volunteers• Bradykinin and substance P caused dose-dependent vasodilatation in the infused forearm (p<0.001). B9340 caused a dose-dependent inhibition of bradykinin-induced forearm vasodilatation and t-PA release (p<0.001) without affecting substance P-induced vasodilatation or t-PA release (p=NS). B9340 caused a reversible inhibition of bradykinin-induced vasodilatation (p<0.001) with a rapid onset and offset of action. Intravenous systemic B9340 administration inhibited the local bradykinin-induced forearm vasodilatation in a dose-dependent mannerIn patients with heart failure• bradykinin and substance P caused dose-dependent vasodilatation and release of t-PA from the infused forearm (p<0.05). Long-term ACE inhibitor therapy caused an increase in forearm vasodilatation (p<0.05) and t-PA release (p<0.001) during bradykinin, but not substance P, infusion.• incremental doses of B9340 caused a dose-dependent reduction in forearm blood flow (p<0.01). After withdrawal of ACE inhibitor therapy, B9340 produced no significant change in forearm blood flow.• systemic intravenous B9340 administration resulted in greater mean arterial pressure, systemic vascular resistance, pulmonary arterial wedge pressure, and mean pulmonary arterial pressure during ACE inhibitor therapy compared with losartan therapy (p<0.005, p<0.07, p<0.0001, and p<0.05 respectively) or placebo infusion (p<0.005 for all).We have shown that bradykinin is a potent vasodilator that stimulates endogenous t-PA release and that these effects are receptor specific and can be blocked by a bradykinin receptor antagonist. We have also shown that bradykinin does not contribute to peripheral or systemic vascular tone in health but does contribute to peripheral and systemic vascular tone in patients with heart failure treated with chronic ACE inhibition. We believe this suggests that many of the beneficial actions of ACE inhibition are mediated through bradykinin

Percutaneous revascularization for ischemic left ventricular dysfunction: Cost-effectiveness analysis of the REVIVED-BCIS2 trial

BACKGROUND: Percutaneous coronary intervention (PCI) is frequently undertaken in patients with ischemic left ventricular systolic dysfunction. The REVIVED (Revascularization for Ischemic Ventricular Dysfunction)-BCIS2 (British Cardiovascular Society-2) trial concluded that PCI did not reduce the incidence of all-cause death or heart failure hospitalization; however, patients assigned to PCI reported better initial health-related quality of life than those assigned to optimal medical therapy (OMT) alone. The aim of this study was to assess the cost-effectiveness of PCI+OMT compared with OMT alone. METHODS: REVIVED-BCIS2 was a prospective, multicenter UK trial, which randomized patients with severe ischemic left ventricular systolic dysfunction to either PCI+OMT or OMT alone. Health care resource use (including planned and unplanned revascularizations, medication, device implantation, and heart failure hospitalizations) and health outcomes data (EuroQol 5-dimension 5-level questionnaire) on each patient were collected at baseline and up to 8 years post-randomization. Resource use was costed using publicly available national unit costs. Within the trial, mean total costs and quality-adjusted life-years (QALYs) were estimated from the perspective of the UK health system. Cost-effectiveness was evaluated using estimated mean costs and QALYs in both groups. Regression analysis was used to adjust for clinically relevant predictors. RESULTS: Between 2013 and 2020, 700 patients were recruited (mean age: PCI+OMT=70 years, OMT=68 years; male (%): PCI+OMT=87, OMT=88); median follow-up was 3.4 years. Over all follow-ups, patients undergoing PCI yielded similar health benefits at higher costs compared with OMT alone (PCI+OMT: 4.14 QALYs, £22 352; OMT alone: 4.16 QALYs, £15 569; difference: −0.015, £6782). For both groups, most health resource consumption occurred in the first 2 years post-randomization. Probabilistic results showed that the probability of PCI being cost-effective was 0. CONCLUSIONS: A minimal difference in total QALYs was identified between arms, and PCI+OMT was not cost-effective compared with OMT, given its additional cost. A strategy of routine PCI to treat ischemic left ventricular systolic dysfunction does not seem to be a justifiable use of health care resources in the United Kingdom

Arrhythmia and death following percutaneous revascularization in ischemic left ventricular dysfunction: Prespecified analyses from the REVIVED-BCIS2 trial

BACKGROUND: Ventricular arrhythmia is an important cause of mortality in patients with ischemic left ventricular dysfunction. Revascularization with coronary artery bypass graft or percutaneous coronary intervention is often recommended for these patients before implantation of a cardiac defibrillator because it is assumed that this may reduce the incidence of fatal and potentially fatal ventricular arrhythmias, although this premise has not been evaluated in a randomized trial to date. METHODS: Patients with severe left ventricular dysfunction, extensive coronary disease, and viable myocardium were randomly assigned to receive either percutaneous coronary intervention (PCI) plus optimal medical and device therapy (OMT) or OMT alone. The composite primary outcome was all-cause death or aborted sudden death (defined as an appropriate implantable cardioverter defibrillator therapy or a resuscitated cardiac arrest) at a minimum of 24 months, analyzed as time to first event on an intention-to-treat basis. Secondary outcomes included cardiovascular death or aborted sudden death, appropriate implantable cardioverter defibrillator (ICD) therapy or sustained ventricular arrhythmia, and number of appropriate ICD therapies. RESULTS: Between August 28, 2013, and March 19, 2020, 700 patients were enrolled across 40 centers in the United Kingdom. A total of 347 patients were assigned to the PCI+OMT group and 353 to the OMT alone group. The mean age of participants was 69 years; 88% were male; 56% had hypertension; 41% had diabetes; and 53% had a clinical history of myocardial infarction. The median left ventricular ejection fraction was 28%; 53.1% had an implantable defibrillator inserted before randomization or during follow-up. All-cause death or aborted sudden death occurred in 144 patients (41.6%) in the PCI group and 142 patients (40.2%) in the OMT group (hazard ratio, 1.03 [95% CI, 0.82–1.30]; P =0.80). There was no between-group difference in the occurrence of any of the secondary outcomes. CONCLUSIONS: PCI was not associated with a reduction in all-cause mortality or aborted sudden death. In patients with ischemic cardiomyopathy, PCI is not beneficial solely for the purpose of reducing potentially fatal ventricular arrhythmias. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01920048

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

AbstractObjectivesThe 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.BackgroundBradykinin is a potent endothelial cell stimulant that causes vasodilatation and t-PA release. In large-scale clinical trials, ACE inhibitor therapy prevents ischemic events.MethodsNine 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.ResultsOn 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 ∼4.5 μg/min.ConclusionsLong-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

Local and Systemic Effects of Intra-arterial Desmopressin in Healthy Volunteers and Patients with Type 3 von Willebrand Disease

SummaryIntra-arterial desmopressin caused dose and time dependent increases (p &lt;0.001 for all) in forearm blood flow (all doses) and plasma tissue plasminogen activator (t-PA) concentrations (desmopressin ≥70 ng/min). Although plasma t-PA concentrations rose in both forearms, there was a modest local release of t-PA in the infused forearm (14 ng/100 mL of tissue/min, p &lt;0.05). At desmopressin doses ≥300 ng/min, plasma von Willebrand factor (vWf) and Factor VIII:C concentrations rose in both forearms (p &lt;0.001) and correlated with the rise in interleukin-6 concentrations (r = 0.92, p &lt;0.001; r = 0.85, p = 0.002 respectively). Neither desmopressin nor substance P caused t-PA, vWf or Factor VIII:C release in the patients, although desmopressin increased plasma interleukin-6 concentrations as in healthy volunteers. We conclude that desmopressin releases t-PA, vWf and Factor VIII:C predominantly via systemic mechanisms, possibly mediated by cytokine release. Patients with type 3 vWD appear to have a generalised failure to release t-PA acutely despite a normal interleukin-6 response to desmopressin infusion.</jats:p