Endothelial dysfunction and glycocalyx shedding in heart failure:insights from patients receiving cardiac resynchronisation therapy

To determine (a) whether chronic heart failure with reduced ejection fraction (HFrEF) is associated with increased glycocalyx shedding; (b) whether glycocalyx shedding in HFrEF with left ventricular dyssynchrony is related to inflammation, endothelial dysfunction and/or redox stress and is ameliorated by cardiac resynchronisation therapy. Glycocalyx shedding has been reported to be increased in heart failure and is a marker of increased mortality. Its role in dyssynchronous systolic heart failure and the effects of cardiac resynchronisation therapy (CRT) are largely unknown. Twenty-six patients with dyssynchronous HFrEF were evaluated before and 6 months after CRT insertion. Echocardiographic septal to posterior wall delay (SPWD) assessed intra-ventricular mechanical dyssynchrony, and quality of life, integrity of nitric oxide (NO) signalling, inflammatory and redox-related biomarkers were measured. Glycocalyx shedding was quantitated via plasma levels of the glycocalyx component, syndecan-1. Syndecan-1 levels pre-CRT were inversely correlated with LVEF (r = - 0.45, p = 0.02) and directly with SPWD (r = 0.44, p = 0.02), QOL (r = 0.39, p = 0.04), plasma NT-proBNP (r = 0.43, p = 0.02), and the inflammatory marker, symmetric dimethylarginine (SDMA) (r = 0.54, p = 0.003). On multivariate analysis, syndecan-1 levels were predicted by SPWD and SDMA (β = 0.42, p = 0.009 and β = 0.54, p = 0.001, respectively). No significant correlation was found between syndecan-1 levels and other markers of endothelial dysfunction/inflammatory activation. Following CRT there was no significant change in syndecan-1 levels. In patients with dyssynchronous HFrEF, markers of glycocalyx shedding are associated with the magnitude of mechanical dyssynchrony and elevation of SDMA levels and inversely with LVEF. However, CRT does not reverse this process

Lack of association between aortic sclerosis and left ventricular hypertrophy in elderly subjects

Methods: 79 subjects, mean age 68 ± 6 years, without existing cardiovascular disease or previous antihypertensive therapy were studied. LV volumes were calculated from the short axis stack of cardiac MRI and LV mass was indexed to height2.7. The presence of aortic sclerosis was assessed with echocardiography using backscatter from the aortic valve (AVBS) and visual scoring. Plasma asymmetric dimethylarginine levels and vascular responses to salbutamol were used to assess endothelial function. ANCOVA was used to test the relationship between LV mass index and afterload. Univariate and multivariate analyses were performed to find determinants of increased LV mass. Results: 15 (19%) of subjects had aortic sclerosis on the basis of AVBS; none had aortic valve areas < 1.5 cm2. There was no significant difference in LV mass between subjects with and without aortic sclerosis. While LV mass was directly related to systolic blood pressure, this relationship was independent of the presence/absence of aortic sclerosis. On multivariate analysis, significant correlates of increased LV mass were male gender, systolic blood pressure and increased BMI, but not presence of aortic sclerosis. Conclusions: In this aging normotensive population free of established cardiovascular disease, aortic sclerosis is not associated with left ventricular hypertrophy.Angus K. Nightingale, Aaron L. Sverdlov, Sharmalar Rajendran, Kumaril Mishra, Tamila Heresztyn, Doan T.M. Ngo, John D. Horowit

Subtle renal dysfunction and bleeding risk in atrial fibrillation : Symmetric dimethylarginine predicts HAS-BLED score

Background: Risk of substantial haemorrhage represents a critically important limitation to effective anti-thrombotic treatment in patients with atrial fibrillation (AF). While it is known that this risk is increased in anticoagulated patients either in the presence of anti-aggregatory drugs or concomitant renal insufficiency, there are currently few data on the potential interactions between endogenous platelet aggregability and bleeding risk. Objective: We therefore evaluated in a cohort of AF patients: (1), the putative relationship between platelet aggregability and HAS-BLED score; (2), the potential biochemical bases for such a relationship. Methods: Patients were included as part of SAFETY, a randomised controlled trial evaluating outpatient management of AF patients. Platelet response to ADP was evaluated via whole blood impedance aggregometry; clinical and biochemical correlates of platelet aggregation were sought via univariate and multivariate analysis. Results: Platelet aggregation correlated inversely (r=-0.220, p < 0.05) with HAS-BLED score. Univariate biochemical correlates of decreased platelet aggregation were plasma concentrations of symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA). On multivariate analyses, plasma SDMA concentration (β=-0.318, p < 0.01), platelet content of thioredoxin-interacting protein (Txnip, β=0.261, p < 0.05) and plasma thrombospondin-1 (TSP-1, β=0.249, p < 0.05) concentration were predictive of platelet ADP response. Consistent with previous reports, plasma SDMA concentrations were strongly and inversely correlated with estimated glomerular filtration rate (eGFR, r=-0.780, p < 0.001). Conclusions: These data therefore suggest that (1), physiologically impaired, like pharmacologically impaired, platelet aggregability may increase bleeding risk in anticoagulated AF patients; (2), the biochemical basis for this may include impaired effects of nitric oxide (via Txnip, TSP-1) but also concomitant renal dysfunction

Ramipril sensitizes platelets to nitric oxide: Implications for therapy in high-risk patients

ObjectivesUsing 2 sequential studies in HOPE (Heart Outcomes Prevention Evaluation) study-type patients, the aims of this study were: 1) to test the hypothesis that ramipril improves platelet nitric oxide (NO) responsiveness: and 2) to explore biochemical and physiological effects of ramipril in a cohort selected on the basis of platelet NO resistance.BackgroundRamipril prevents cardiovascular events, but the bases for these effects remain uncertain. NO resistance at both the platelet and vascular levels is present in a substantial proportion of patients with diabetes or ischemic heart disease and is an independent risk factor for cardiovascular events.MethodsStudy 1 was a double-blind, randomized comparison of ramipril (10 mg) with placebo in a cohort of patients (n = 119) with ischemic heart disease or diabetes plus additional coronary risk factor(s), in which effects on platelet responsiveness to NO were compared. Study 2 was a subsequent short-term evaluation of the effects of ramipril in a cohort of subjects (n = 19) with impaired platelet NO responsiveness in whom additional mechanistic data were sought.ResultsIn study 1, ramipril therapy increased platelet responsiveness to NO relative to the extent of aggregation (p ConclusionsRamipril ameliorates platelet NO resistance in HOPE study-type patients, with associated increases in soluble guanylate cyclase responsiveness to NO. This effect is likely to contribute to treatment benefit and define patients in whom ramipril therapy is particularly effective.Scott R. Willoughby, Sharmalar Rajendran, Wai P. Chan, Nathan Procter, Sue Leslie, Elizabeth A. Liberts, Tamila Heresztyn, Yuliy Y. Chirkov, John D. Horowit

Asymmetric and symmetric dimethylarginine predict outcomes in patients with atrial fibrillation: an ARISTOTLE substudy

Abstract not availableJohn D. Horowitz, Raffaele De Caterina, Tamila Heresztyn, John H. Alexander, Ulrika Andersson, Renato D. Lopes ... et al

Impaired platelet nitric oxide response in patients with new onset atrial fibrillation

Background: Clinical factors associated with thromboembolic risk in AF patients are well characterized and include new onset AF. Biochemically, AF is associated with inflammatory activation and impairment of nitric oxide (NO) signalling, which may also predispose to thromboembolism: the bases for variability in these anomalies have not been identified. We therefore sought to identify correlates of impaired platelet NO signalling in patients hospitalized with atrial fibrillation (AF), and to evaluate the impact of acuity of AF. Methods: 87 patients hospitalized with AF were evaluated. Platelet aggregation, and its inhibition by the NO donor sodium nitroprusside, was evaluated using whole blood impedance aggregometry. Correlates of impaired NO response were examined and repeated in a “validation” cohort of acute cardiac illnesses. Results: Whilst clinical risk scores were not significantly correlated with integrity of NO signalling, new onset AF was associated with impaired NO response (6 ± 5% inhibition versus 25 ± 4% inhibition for chronic AF, p < 0.01). New onset AF was a multivariate correlate (p < 0.01) of impaired NO signalling, along with platelet ADP response (p < 0.001), whereas the associated tachycardia was not. Platelet ADP response was predicted by elevation of plasma thrombospondin-1 concentrations (p < 0.01). Validation cohort evaluations confirmed that acute AF was associated with significant (p < 0.05) impairment of platelet NO response, and that neither acute heart failure nor acute coronary syndromes were associated with similar impairment. Conclusion: Recent onset of AF is associated with marked impairment of platelet NO response. These findings may contribute to thromboembolic risk in such patients

Impaired platelet nitric oxide response in patients with new onset atrial fibrillation

Background: Clinical factors associated with thromboembolic risk in AF patients are well characterized and include new onset AF. Biochemically, AF is associated with inflammatory activation and impairment of nitric oxide (NO) signalling, which may also predispose to thromboembolism: the bases for variability in these anomalies have not been identified. We therefore sought to identify correlates of impaired platelet NO signalling in patients hospitalized with atrial fibrillation (AF), and to evaluate the impact of acuity of AF. Methods: 87 patients hospitalized with AF were evaluated. Platelet aggregation, and its inhibition by the NO donor sodium nitroprusside, was evaluated using whole blood impedance aggregometry. Correlates of impaired NO response were examined and repeated in a “validation” cohort of acute cardiac illnesses. Results: Whilst clinical risk scores were not significantly correlated with integrity of NO signalling, new onset AF was associated with impaired NO response (6 ± 5% inhibition versus 25 ± 4% inhibition for chronic AF, p < 0.01). New onset AF was a multivariate correlate (p < 0.01) of impaired NO signalling, along with platelet ADP response (p < 0.001), whereas the associated tachycardia was not. Platelet ADP response was predicted by elevation of plasma thrombospondin-1 concentrations (p < 0.01). Validation cohort evaluations confirmed that acute AF was associated with significant (p < 0.05) impairment of platelet NO response, and that neither acute heart failure nor acute coronary syndromes were associated with similar impairment. Conclusion: Recent onset of AF is associated with marked impairment of platelet NO response. These findings may contribute to thromboembolic risk in such patients