Inhibition of kinin metabolism and the role of the vascular B₁ kinin receptor in patients with congestive heart failure

BACKGROUND Angiotensin-converting enzyme and neutral endopeptidase are endothelial metallopeptidases that metabolise bradykinin. Inhibitors of angiotensinconverting enzyme improve symptoms and survival in patients with heart failure and vascular disease and potentiate bradykinin-mediated vasodilatation and endothelial tissue plasminogen activator release. The vascular actions of kinins are mediated by an inducible B₁ receptor and a constitutively expressed B₂ receptor. Vascular B₁ kinin receptor expression is markedly upregulated with left ventricular dysfunction and angiotensin-converting enzyme inhibition, but its role in man remains unclear.OBJECTIVES The aims of this thesis were first, to confirm biological activity of kinin receptor agonists and antagonists in human vascular tissue in vitro: second, to determine the contribution of bradykinin to the systemic haemodynamic effects of angiotensin-converting enzyme inhibition in patients with heart failure: third, to determine the effects of neutral endopeptidase inhibition on the vascular actions of bradykinin in patients treated with angiotensin-converting enzyme inhibition: fourth and finally, to determine the contribution of the B₁ kinin receptor to the vascular actions of kinins in patients with heart failureMETHODS Myography The vasomotor effects of kinin peptides were determined using myography of human umbilical vein rings. Heart failure: Systemic circulation After 6 weeks of enalapril or losartan therapy, patients underwent right heart catheterisation and received an intravenous infusion of the bradykinin receptor antagonist, B9340. Systemic haemodynamic variables were recorded. Peripheral circulation Blood flow and plasma fibrinolytic parameters were determined in both forearms using venous occlusion plethysmography and venous blood sampling. Drugs were administered via the brachial artery of the non-dominant forearm. The effect of the neutral endopeptidase inhibitor, thiorphan, on the vascular actions of bradykinin was examined in patients maintained on angiotensin-converting enzyme inhibition. Vascular Bi receptor function was examined using selective peptidic kinin receptor agonists and antagonists.RESULTS Biological activity of kinin receptor agonists and antagonists was confirmed in human umbilical vein. Systemic bradykinin antagonism caused an increase in mean arterial pressure and systemic vascular resistance and attenuated the fall in pulmonary arterial and pulmonary arterial wedge pressures in patients treated with enalapril compared to losartan. Compared to placebo, thiorphan augmented the vasomotor and fibrinolytic actions of bradykinin in patients treated with chronic angiotensin-converting enzyme inhibition. Bi receptor agonism and antagonism had no effect on vascular tone or enothelial tissue plasminogen activator release in the presence or absence of angiotensin-converting enzyme inhibition. The B2 receptor agonist, bradykinin, caused vasodilatation and tissue plasminogen activator release and these effects were markedly augmented by angiotensin-converting enzyme inhibition.CONCLUSIONS Bradykinin contributes to the systemic haemodynamic effects of longterm angiotensin-converting enzyme inhibition in patients with heart failure. Neutral endopeptidase contributes to the metabolism of bradykinin in patients with heart failure maintained on angiotensin-converting enzyme inhibitor therapy. Our findings may explain some of the apparent clinical differences between angiotensinconverting enzyme inhibitors and angiotensin receptor blockers, as well as the greater vasodepressor effect observed with combined angiotensin-converting enzyme and neutral endopeptidase inhibition when compared to angiotensin-converting enzyme inhibition alone. Finally, the B₁ kinin receptor does not appear to have a major vasomotor or fibrinolytic role in patients with heart failure. Augmentation of kinin-mediated vasodilatation and tissue plasminogen activator release by angiotensin-converting enzyme inhibition is restricted to the B₂ recepto

A low-dose comprehensive cardiac CT protocol assessing anatomy, function, perfusion, and viability

AbstractRadiation exposure in cardiac imaging is a major healthcare concern and low-dose cardiac imaging has important implications for patients. We describe the application of a low-dose comprehensive cardiac computed tomography protocol that assesses anatomy, function, perfusion and viability with correlations to invasive coronary angiography and magnetic resonance imaging

Ischaemia-reperfusion injury impairs tissue plasminogen activator release in man

AIMS: Ischaemia-reperfusion (IR) injury causes endothelium-dependent vasomotor dysfunction that can be prevented by ischaemic preconditioning. The effects of IR injury and preconditioning on endothelium-dependent tissue plasminogen activator (t-PA) release, an important mediator of endogenous fibrinolysis, remain unknown. METHODS AND RESULTS: Ischaemia-reperfusion injury (limb occlusion at 200 mmHg for 20 min) was induced in 22 healthy subjects. In 12 subjects, IR injury was preceded by local or remote ischaemic preconditioning (three 5 min episodes of ipsilateral or contralateral limb occlusion, respectively) or sham in a randomized, cross-over trial. Forearm blood flow (FBF) and endothelial t-PA release were assessed using venous occlusion plethysmography and venous blood sampling during intra-arterial infusion of acetylcholine (5-20 µg/min) or substance P (2-8 pmol/min). Acetylcholine and substance P caused dose-dependent increases in FBF (P<0.05 for all). Substance P caused a dose-dependent increase in t-PA release (P<0.05 for all). Acetylcholine and substanceP-mediated vasodilatation and substanceP-mediated t-PA release were impaired following IR injury (P<0.05 for all). Neither local nor remote ischaemic preconditioning protected against the impairment of substance P-mediated vasodilatation or t-PA release. CONCLUSION: Ischaemia-reperfusion injury induced substanceP-mediated, endothelium-dependent vasomotor and fibrinolytic dysfunction in man that could not be prevented by ischaemic preconditioning. CLINICAL TRIAL REGISTRATION INFORMATION: Reference number: NCT00789243, URL: http://clinicaltrials.gov/ct2/show/NCT00789243?term=NCT00789243andrank=1

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

<p>Abstract</p> <p>Introduction</p> <p>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.</p> <p>Case presentation</p> <p>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.</p> <p>Conclusion</p> <p>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.</p

Rotigaptide protects the myocardium and arterial vasculature from ischaemia reperfusion injury

Aim: Ischaemia-reperfusion injury (IRI) causes impaired endothelial function and is a major component of the adverse effects of reperfusion following myocardial infarction. Rotigaptide increases gap junction conductance via connexin-43. We tested the hypothesis that rotigaptide reduces experimental myocardial infarction size and ameliorates endothelial IRI in humans. Methods: Myocardial infarction study: porcine myocardial infarction was achieved by catheter-induced occlusion of the left anterior descending artery. In a randomized double-blind study, rotigaptide (n = 9) or placebo (n = 10) was administered intravenously as a 10 min bolus prior to reperfusion and continuously during 2 h of reperfusion. Myocardial infarction size (IS) was assessed as proportion of the area at risk (AAR). Human translational study: forearm IRI was induced in the presence or absence of intra-arterial rotigaptide. In a randomized double-blind study, forearm arterial blood flow was measured at rest and during intra-arterial infusion of acetylcholine (5–20 μg min–1; n = 11) or sodium nitroprusside (2–8 mg min–1; n = 10) before and after intra-arterial infusion of placebo or rotigaptide, and again following IRI. Results: Myocardial infarction study: Rotigaptide treatment was associated with a reduction of infarct size (IS/AAR[%]: 18.7 ± 4.1 [rotigaptide] vs. 43.6 ± 4.2 [placebo], P = 0.006). Human translational study: Endothelium-dependent vasodilatation to acetylcholine was attenuated after ischaemia-reperfusion in the presence of placebo (P = 0.007), but not in the presence of rotigaptide (P = NS). Endothelium-independent vasodilatation evoked by sodium nitroprusside was unaffected by IRI or rotigaptide (P = NS). Conclusions: Rotigaptide reduces myocardial infarction size in a porcine model and protects from IRI-related endothelial dysfunction in man. Rotigaptide may have therapeutic potential in the treatment of myocardial infarction

Optical coherence tomography versus intravascular ultrasound to evaluate stent implantation in patients with calcific coronary artery disease

AIMS: Stent underexpansion and malapposition are associated with adverse outcomes following percutaneous coronary intervention, but detection and treatment can be challenging in the presence of extensive coronary artery calcification. Frequency domain optical coherence tomography (FD-OCT) is a novel intravascular imaging technique with greater spatial resolution than intravascular ultrasound (IVUS) but its role in the presence of extensive coronary calcification remains unclear. We sought to determine the utility of FD-OCT compared to IVUS imaging to guide percutaneous coronary intervention in patients with severe calcific coronary artery disease. METHODS: 18 matched IVUS and FD-OCT examinations were evaluated following coronary stent implantation in 12 patients (10 male; mean age 70±7 years) undergoing rotational atherectomy for symptomatic calcific coronary artery disease. RESULTS: In-stent luminal areas were smaller (minimum in-stent area 6.77±2.18 vs 7.19±2.62 mm(2), p<0.05), while reference lumen dimensions were similar with FD-OCT compared with IVUS. Stent malapposition was detected in all patients by FD-OCT and in 10 patients by IVUS. The extent of stent malapposition detected was greater (20% vs 6%, p<0.001) with FD-OCT compared to IVUS. Postdilation increased the in-stent luminal area (minimum in-stent area: 8.15±1.90 vs 7.30±1.62 mm(2), p<0.05) and reduced the extent of stent malapposition (19% vs 34%, p<0.005) when assessed by FD-OCT, but not IVUS. CONCLUSIONS: Acute stent malapposition occurs frequently in patients with calcific coronary disease undergoing rotational atherectomy and stent implantation. In the presence of extensive coronary artery calcification, FD-OCT affords enhanced stent visualisation and detection of malapposition, facilitating improved postdilation stent apposition and minimal luminal areas. TRIAL REGISTRATION NUMBER: NCT02065102

Vascular effects of apelin in vivo in man

ObjectivesThis study was designed to establish the direct vascular effects of apelin in vivo in man.BackgroundApelin is the endogenous ligand for the previously orphaned G-protein–coupled receptor, APJ. This novel pathway is widely expressed in the cardiovascular system and is emerging as an important mediator of cardiovascular homeostasis. In pre-clinical models, apelin causes venous and arterial vasodilation.MethodsVascular effects of apelin were assessed in 24 healthy volunteers. Dorsal hand vein diameter was measured by the Aellig technique during local intravenous infusions (0.1 to 3 nmol/min) of apelin-36, (Pyr1)apelin-13, and sodium nitroprusside (0.6 nmol/min). Forearm blood flow was measured by venous occlusion plethysmography during intrabrachial infusions of apelin-36 and (Pyr1)apelin-13 (0.1 to 30 nmol/min) and subsequently in the presence or absence of a “nitric oxide clamp” (nitric oxide synthase inhibitor, L-NG-monomethylarginine [8 μmol/min], coinfused with nitric oxide donor, sodium nitroprusside [90 to 900 ng/min]), or a single oral dose of aspirin (600 mg) or matched placebo.ResultsAlthough sodium nitroprusside caused venodilation (p < 0.0001), apelin-36 and (Pyr1)apelin-13 had no effect on dorsal hand vein diameter (p = 0.2). Both apelin isoforms caused reproducible vasodilation in forearm resistance vessels (p < 0.0001). (Pyr1)apelin-13–mediated vasodilation was attenuated by the nitric oxide clamp (p = 0.004) but unaffected by aspirin (p = 0.7).ConclusionsAlthough having no apparent effect on venous tone, apelin causes nitric oxide–dependent arterial vasodilation in vivo in man. The apelin-APJ system merits further clinical investigation to determine its role in cardiovascular homeostasis

Incidence, Microbiology, and Outcomes in Patients Hospitalized With Infective Endocarditis.

BACKGROUND: Despite improvements in management, infective endocarditis remains associated with high mortality and morbidity. We describe temporal changes in the incidence, microbiology, and outcomes of infective endocarditis and the effect of changes in national antibiotic prophylaxis guidelines on incident infective endocarditis. METHODS: Using a Scotland-wide, individual-level linkage approach, all patients hospitalized with infective endocarditis from 1990 to 2014 were identified and linked to national microbiology, prescribing, and morbidity and mortality datasets. Linked data were used to evaluate trends in the crude and age- and sex-adjusted incidence and outcomes of infective endocarditis hospitalizations. From 2008, microbiology data and associated outcomes adjusted for patient demographics and comorbidity were also analyzed. An interrupted time series analysis was performed to evaluate incidence before and after changes to national antibiotic prophylaxis guidelines. RESULTS: There were 7638 hospitalizations (65±17 years, 51% females) with infective endocarditis. The estimated crude hospitalization rate increased from 5.3/100 000 (95% CI, 4.8-5.9) to 8.6/100 000 (95% CI, 8.1-9.1) between 1990 and 1995 but remained stable thereafter. There was no change in crude incidence following the 2008 change in antibiotic prophylaxis guidelines (relative risk of change 1.06 [95% CI, 0.94-1.20]). The incidence rate in patients >80 years of age doubled from 1990 to 2014 (17.7/100 000 [95% CI, 13.4-23.3] to 37.9/100 000 [95% CI, 31.5-45.5]). The predicted 1-year age- and comorbidity-adjusted case fatality rate for a 65-year-old patient decreased in women (27.3% [95% CI, 24.6-30.2] to 23.7% [95% CI, 21.1-26.6]) and men (30.7% [95% CI, 27.7-33.8] to 26.8% [95% CI, 24.0-29.7]) from 1990 to 2014. Blood culture data were available from 2008 (n=2267/7638, 30%), with positive blood cultures recorded in 42% (950/2267). Staphylococcus (403/950, 42.4%) and streptococcus (337/950, 35.5%) species were most common. Staphylococcus aureus and enterococcus had the highest 1-year mortality (adjusted odds ratio 4.34 [95% CI, 3.12-6.05] and 3.41 [95% CI, 2.04-5.70], respectively). CONCLUSIONS: Despite changes in antibiotic prophylaxis guidelines, the crude incidence of infective endocarditis has remained stable. However, the incidence rate has doubled in the elderly. Positive blood cultures were observed in less than half of patients, with Staphylococcus aureus and enterococcus bacteremia associated with worse outcomes