Endogenous Fibrinolysis : An Important Mediator of Thrombus Formation and Cardiovascular Risk

© 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION. PUBLISHED BY ELSEVIER INC.Most acute cardiovascular events are attributable to arterial thrombosis. Plaque rupture or erosion stimulates platelet activation, aggregation, and thrombosis, whilst simultaneously activating enzymatic processes that mediate endogenous fibrinolysis to physiologically maintain vessel patency. Interplay between these pathways determines clinical outcome. If proaggregatory factors predominate, the thrombus may propagate, leading to vessel occlusion. However, if balanced by a healthy fibrinolytic system, thrombosis may not occur or cause lasting occlusion. Despite abundant evidence for the fibrinolytic system regulating thrombosis, it has been overlooked compared with platelet reactivity, partly due to a lack of techniques to measure it. We evaluate evidence for endogenous fibrinolysis in arterial thrombosis and review techniques to assess it, including biomarkers and global assays, such as thromboelastography and the Global Thrombosis Test. Global assays, simultaneously assessing proaggregatory and fibrinolytic pathways, could play a role in risk stratification and in identifying impaired fibrinolysis as a potential target for pharmacological modulation.Peer reviewedFinal Published versio

Vectorcardiographic evaluation of electrical dyssynchrony and its role in predicting response to cardiac resynchronization therapy

[Doctor of Medicine thesis]. Cardiac resynchronization therapy (CRT) has become an important therapeutic strategy for heart failure (HF) patients with impaired left ventricular (LV) systolic function and prolonged QRS duration. The benefit of CRT as an adjunct to pharmacological therapy is now well established, with sustained improvements in quality of life, hospitalization rates and mortality. However, even in carefully selected patients, the response to CRT is often unpredictable with a considerable number of nonresponders (30-50%). Although the reasons for this nonresponse are not entirely clear, studies have suggested that non-optimal left ventricular (LV) lead positioning, lack of electrical dyssynchrony, suboptimal device programming and myocardial scar burden play an important role. More recently, a wealth of evidence has pointed to the limitations of 12-lead electrocardiography, suggesting it may not accurately reflect the presence or complexities of electrical dyssynchrony in the failing heart. As the efficacy of CRT is primarily achieved through LV resynchronization, there has been renewed interest in the development of techniques that enable better characterization of cardiac electric activation patterns and identification of electrical dyssynchrony. This approach would appear logical, given that CRT is primarily an ‘electrical therapy’, designed to treat an underlying electrical conduction abnormality. Vectorcardiography (VCG), which was first described in 1920, offers an alternative interpretation of the 12-lead ECG. Its resurgence in the field of CRT has emerged from the recognition that VCG parameters can provide information on dyssynchrony beyond that currently provided by the 12-lead ECG. Prominent amongst these is vectorcardiographic QRS area (QRSarea), which has been shown to be superior to QRSd and QRS morphology in predicting response to CRT. The work presented herein is structured into two major sections. First, we investigate the role of QRSarea as a novel predictor of response to CRT. Using a combination of different study designs, our results demonstrate that QRSarea is a better predictor of CRT response than QRSd and QRS morphology. We also show that CRT-induced ΔQRSarea can be used to help quantify LV resynchronization and to predict long-term clinical outcomes following CRT. Importantly, we are the first to show that a concomitant reduction in both QRSarea and QRSd is associated with the best clinical outcomes after CRT, indicating that ECG and VCG can be used in conjunction to help improve patient selection for CRT. In the second part of this thesis, we focus on the development and validation of a novel, vector-based 3D electroanatomical modelling system. Using a novel computational method, ECGSync combines the surface ECG-derived vectorcardiogram with cardiac magnetic resonance imaging to estimate, by inverse solution, the 3-dimensional sequence of LV activation. Accordingly, we show that ECGSync can noninvasively map ventricular electrical activity and accurately locate the site of latest electrical activation prior to CRT implantation. Furthermore, we demonstrate that novel ECGSync-derived markers of dyssynchrony can help predict CRT response. Our findings suggest that VCG may have great potential to improve the clinical application of CRT

The Impact of Poverty on Senior Secondary School Girls’ Prospect for Tertiary Education in Nigeria

Poverty has degraded lives for centuries; and human deprivation is still persistent in the developing countries of the world. It is in this regard that this study examined the impact of poverty on senior secondary school girls’ prospect for tertiary education in Nigeria. The aim was to ascertain the extent to which the prospect of senior secondary school girls for tertiary education is susceptible to poverty. The study was conducted adopting empirical design. The data used for the study were time series data. A stochastic model was specified for the study to show the impact of poverty on senior secondary school girls’ prospect for tertiary education in Nigeria during the period under study (1992 – 2011). The ordinary least square (OLS) regression technique with econometric views 3 software was used to analyze the study’s data. The estimated result showed that both poverty and unemployment are significant determinants of senior secondary school girls’ prospect for tertiary education in Nigeria. It is therefore suggested among other things that Governments should not only direct policy actions towards encouraging the education of the girls from poor homes by creating separate scholarship platforms for them that can fund their education from secondary school to university level; but also should extend the free education policy to secondary school level in order to give every child from a poor home the opportunity to have at least secondary education. This would help to reduce the girl-child trafficking for sex work, as well as all poverty stimulated juvenile delinquencies in the country

Relative effects of different non-vitamin K antagonist oral anticoagulants on global thrombotic status in atrial fibrillation

This is an Accepted Manuscript of an article published by Taylor & Francis GroupNon-vitamin K antagonist oral anticoagulants (NOACs) reduce the risk of thromboembolism in patients with atrial fibrillation (AF). There has been no head-to-head comparison of the effect of these agents on ex vivo thrombotic and thrombolytic status. Enhanced platelet reactivity and impaired endogenous thrombolysis are risk factors for recurrent thrombotic events. We aimed to assess the comparative effect of NOACs and warfarin using an ex vivo test of thrombosis and thrombolysis. Eighty patients with newly diagnosed non-valvular AF were tested before, and after being established on apixaban (n = 20), dabigatran (n = 20), rivaroxaban (n = 20), or warfarin (n = 20). Thrombotic status was assessed with the automated, point-of-care Global Thrombosis Test (GTT) that assesses both platelet reactivity and endogenous thrombolysis from native blood. The time taken to form an occlusive thrombus (occlusion time, OT) and the time required to restore flow through endogenous thrombolysis (lysis time, LT) were measured. All anticoagulants caused OT prolongation compared to baseline (apixaban 403 ± 102s vs. 496 ± 125s, p = 0.006; dabigatran 471 ± 106s vs. 656 ± 165s, p < 0.00001; rivaroxaban 381 ± 119s vs. 579 ± 158, p < 0.00001; warfarin 420 ± 145s vs. 604 ± 124s, p < 0.00001). Apixaban reduced LT from baseline (1895[1702-2167]s vs. 1435[347-1990]s; p = 0.006). A trend for LT reduction was seen with other NOACs (dabigatran 1594[1226-2069]s vs. 1539[561-2316]s, p = 0.499; rivaroxaban 2085[1366-2428]s vs. 1885[724-2420]s, p = 0.295) but not with warfarin (1490[1206-1960]s vs. 1776[1545-2334], p = 0.601). Our results suggest that NOACs and warfarin have a similar favorable effect on reducing platelet reactivity. All NOACs exhibited a trend toward enhancing endogenous thrombolytic status, although this was significant only for apixaban. This raises the possibility of using NOACs to enhance impaired endogenous fibrinolysis in patients at high-thrombotic risk.Peer reviewedFinal Accepted Versio

Changes in QRS Area and QRS Duration After Cardiac Resynchronization Therapy Predict Cardiac Mortality, Heart Failure Hospitalizations, and Ventricular Arrhythmias

Background Predicting clinical outcomes after cardiac resynchronization therapy (CRT) and its optimization remain a challenge. We sought to determine whether pre- and postimplantation QRS area (QRS area) predict clinical outcomes after CRT. Methods and Results In this retrospective study, QRS area, derived from pre- and postimplantation vectorcardiography, were assessed in relation to the primary end point of cardiac mortality after CRT with or without defibrillation. Other end points included total mortality, total mortality or heart failure (HF) hospitalization, total mortality or major adverse cardiac events, and the arrhythmic end point of sudden cardiac death or ventricular arrhythmias with or without a shock. In patients (n=380, age 72.0±12.4 years, 68.7% male) undergoing CRT over 7.7 years (median follow-up: 3.8 years [interquartile range 2.3-5.3]), preimplantation QRS area ≥102 μVs predicted cardiac mortality (HR: 0.36; P<0.001), independent of QRS duration (QRSd) and morphology ( P<0.001). A QRS area reduction ≥45 μVs after CRT predicted cardiac mortality (HR: 0.19), total mortality (HR: 0.50), total mortality or heart failure hospitalization (HR: 0.44), total mortality or major adverse cardiac events (HR: 0.43) (all P<0.001) and the arrhythmic end point (HR: 0.26; P<0.001). A concomitant reduction in QRS area and QRSd was associated with the lowest risk of cardiac mortality and the arrhythmic end point (both HR: 0.12, P<0.001). Conclusions Pre-implantation QRS area, derived from vectorcardiography, was superior to QRSd and QRS morphology in predicting cardiac mortality after CRT. A postimplant reduction in both QRS area and QRSd was associated with the best outcomes, including the arrhythmic end point

Survival after cardiac resynchronization therapy: results from 50 084 implantations

Aims Randomized controlled trials have shown that cardiac resynchronization therapy (CRT) prolongs survival in patients with heart failure. No studies have explored survival after CRT in relation to individuals in the general population (relative survival, RS). We sought to determine observed and RS after CRT in a nationwide cohort undergoing CRT. Methods and results A national administrative database was used to quantify observed mortality for patients undergoing CRT. Relative survival (RS) was quantified using life tables. In 50 084 patients [age 72.1 ± 11.6 years (mean ± standard deviation)] undergoing CRT with (CRT-D) (n = 25 273) or without (CRT-P) defibrillation (n = 24 811) over 8.8 years (median follow-up 2.7 years, interquartile range 1.3–4.8), expected survival decreased with age. Device type, male sex, ischaemic heart disease, diabetes, and chronic kidney disease predicted excess mortality. In multivariate analyses, excess mortality (analogue of RS) was lower after CRT-D than after CRT-P in all patients [adjusted hazard ratio (aHR) 0.80, 95% confidence interval (CI) 0.76–0.84] as well as in subgroups with (aHR 0.79, 95% CI 0.74–0.84) or without (aHR 0.82, 95% CI 0.74–0.91) ischaemic heart disease. A Charlson Comorbidity Index (CCI) ≥3 portended a higher excess mortality (aHR 3.04, 95% CI 2.76–3.34). Relative survival was higher in 2015–2017 than in 2009–2011 (aHR 0.64, 95% CI 0.59–0.69). Conclusion Reference RS data after CRT is presented. Sex, ischaemic heart disease, diabetes, chronic kidney disease, and CCI were major determinants of RS after CRT. CRT-D was associated with a higher RS than CRT-P in patients with or without ischaemic heart disease. Relative survival after CRT improved from 2009 to 2017

Cardiac operations and interventions during the COVID-19 pandemic: a nationwide perspective

AIMS : The COVID-19 pandemic has led to a decline in hospitalizations for non-COVID-19-related conditions. We explored the impact of the COVID-19 pandemic on cardiac operations and interventions undertaken in England. METHODS AND RESULTS : An administrative database covering hospital activity for England, the Health Episodes Statistics, was used to assess a total of 286 697 hospitalizations for cardiac operations and interventions, as well as 227 257 hospitalizations for myocardial infarction (MI) and 453 799 for heart failure (HF) from 7 January 2019 to 26 July 2020. Over the 3 months of 'lockdown', total numbers and mean reductions in weekly rates [n (-%)], compared with the same time period in 2019, were: coronary artery bypass grafting [-2507 (-64%)]; percutaneous coronary intervention [-5245 (-28%)]; surgical [-1324 (-41%)] and transcatheter [-284 (-21%)] aortic valve replacement; mitral valve replacement; implantation of pacemakers [-6450 (-44%)], cardiac resynchronization therapy with [-356 (-42%)] or without [-491 (-46%)] defibrillation devices, and implantable cardioverter-defibrillators [-501 (-45%)]; atrial fibrillation ablation [-1902 (-83%)], and other ablations [-1712 (-64%)] (all P < 0.001). Over this period, there were 21 038 fewer procedures than in the reference period in 2019 (P < 0.001). These changes paralleled reductions in hospitalizations for MI [-10 794 (-27%)] and HF [-63 058 (-28%)] (both P < 0.001). CONCLUSIONS : The COVID-19 pandemic has led to substantial reductions in the number of cardiac operations and interventions undertaken. An alternative strategy for healthcare delivery to patients with cardiac conditions during the COVID-19 pandemic is urgently needed

Generalized lymphadenopathy: an unusual presentation of burkitt lymphoma in a Nigerian child: a case report

Intoduction: Burkitt Lymphoma is the fastest growing tumor in human and the commonest of the childhood malignancies. Generalized lymphadenopathy is a common feature of immunodeficiency associated Burkitt lymphoma but an uncommon presentation of the endemic type in Human Immunodeficiency Virus (HIV) negative children. Case presentation: The authors report a 6 year old HIV negative boy who presented with generalized lymphadenopathy, cough, weight loss, fever and drenching night sweat and had received native medication as well as treatment in private hospitals. His examination revealed hepatosplenomegaly, bull neck with generalized significant massive lymphadenopathy. Diagnosis was missed initially until a lymphnode biopsy for histology confirmed Burkitt lymphoma. He was managed on combination chemotherapy with complete resolution and now on follow up. Conclusion: To the best of our knowledge, this is the first documented report of its kind of endemic Burkitt lymphoma involving lymphnodes generally as the primary site. High index of suspicion and early biopsy are the key in this uncommon presentation

Greyzone myocardial fibrosis and ventricular arrhythmias in patients with a left ventricular ejection fraction >35%

AIMS: To determine whether myocardial fibrosis and greyzone fibrosis (GZF) on cardiovascular magnetic resonance (CMR) is associated with ventricular arrhythmias in patients with coronary artery disease (CAD) and a left ventricular ejection fraction (LVEF) >35%. METHODS AND RESULTS: In this retrospective study of CAD patients, GZF mass using the 3SD method (GZF3SD) and total fibrosis mass using the 2SD method (TF2SD) on CMR were assessed in relation to the primary, combined endpoint of sudden cardiac death, ventricular tachycardia, ventricular fibrillation, or resuscitated cardiac arrest. Among 701 patients [age: 65.8 ± 12.3 years (mean ± SD)], 28 (3.99%) patients met the primary endpoint over 5.91 years (median; interquartile range 4.42-7.64). In competing risks analysis, a GZF3SD mass ≥5.0 g was strongly associated with the primary endpoint [subdistribution hazard ratio (sHR): 17.4 (95% confidence interval, CI 6.64-45.5); area under receiver operator characteristic curve (AUC): 0.85, P 35%, GZF3SD mass was strongly associated with the arrhythmic endpoint. These findings hold promise for its use in identifying patients with CAD and an LVEF >35% at risk of arrhythmic events

Acute Hemodynamic Effects of Simultaneous and Sequential Multi-Point Pacing in Heart Failure Patients With an Expected Higher Rate of Sub-response to Cardiac Resynchronization Therapy: Results of Multicenter SYNSEQ Study

The aim of the SYNSEQ (Left Ventricular Synchronous vs. Sequential MultiSpot Pacing for CRT) study was to evaluate the acute hemodynamic response (AHR) of simultaneous (3P-MPP syn) or sequential (3P-MPP seq) multi-3-point-left-ventricular (LV) pacing vs. single point pacing (SPP) in a group of patients at risk of a suboptimal response to cardiac resynchronization therapy (CRT). Twenty five patients with myocardial scar or QRS ≤ 150 or the absence of LBBB (age: 66 ± 12 years, QRS: 159 ± 12 ms, NYHA class II/III, LVEF ≤ 35%) underwent acute hemodynamic assessment by LV + dP/dtmax with a variety of LV pacing configurations at an optimized AV delay. The change in LV + dP/dt max (%ΔLV + dP/dt max) with 3P-MPP syn (15.6%, 95% CI: 8.8%-22.5%) was neither statistically significantly different to 3P-MPP seq (11.8%, 95% CI: 7.6-16.0%) nor to SPP basal (11.5%, 95% CI:7.1-15.9%) or SPP mid (12.2%, 95% CI:7.9-16.5%), but higher than SPP apical (10.6%, 95% CI:5.3-15.9%, p = 0.03). AHR (defined as a %ΔLV + dP/dt max ≥ 10%) varied between pacing configurations: 36% (9/25) for SPP apical, 44% (11/25) for SPP basal, 54% (13/24) for SPP mid, 56% (14/25) for 3P-MPP syn and 48% (11/23) for 3P-MPP seq.Fifteen patients (15/25, 60%) had an AHR in at least one pacing configuration. AHR was observed in 10/13 (77%) patients with a LBBB but only in 5/12 (42%) patients with a non-LBBB (p = 0.11). To conclude, simultaneous or sequential multipoint pacing compared to single point pacing did not improve the acute hemodynamic effect in a suboptimal CRT response population. Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT02914457