Simon G Williams

University Hospital Of South Manchester NHS Foundation Trust, Manchester, England, United Kingdom

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Publications (39)206.18 Total impact

  • Parminder S Chaggar, Chris Skene, Simon G Williams
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    ABSTRACT: Cardiac resynchronization (CRT) is a well-established treatment for heart failure and standard superior implantation has a high success rate with acceptable risk profile. When the superior approach is not feasible, surgical epicardial leads are considered. We present a case of transfemoral CRT as a viable alternative to surgical systems and discuss implant factors including lead choice and deep vein thrombosis. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.
    12/2014;
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    ABSTRACT: AimsWe wish to assess the clinical and cost-effectiveness of remote monitoring of heart failure patients with cardiac implanted electronic devices.MethodsREM-HF is a multicentre, randomized, non-blinded, parallel trial designed to compare weekly remote monitoring-driven management with usual care for patients with cardiac implanted electronic devices (ICD, CRT-D, or CRT-P). The trial is event driven, and the final analysis will be performed when 546 events have been observed or the study is terminated at the interim analysis. We have randomized 1650 patients to be followed up for a minimum of 2 years. Patients will remain in the trial up to study termination. The first patient was randomized in September 2011 and the study is expected to complete in early 2016. The primary combined endpoint is time to first event of all-cause death or unplanned hospitalization for cardiovascular reasons. An economic evaluation will be performed, estimating the cost per quality-adjusted lifeyear, with direct costs estimated from the National Health Service perspective and quality of life assessed by the EQ-5D, Short-Form12, and Kansas City Cardiomyopathy Questionnaires. The study design has been informed by a feasibility study.ConclusionREM-HF is a multicentre randomized study that will provide important data on the effect of remote monitoring-driven management of implanted cardiac devices on morbidity and mortality, as well as the cost-effectiveness of this approach.Trial registration: UKCRN 10383.
    European Journal of Heart Failure 08/2014; · 5.25 Impact Factor
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    ABSTRACT: To evaluate the diagnostic performance of multiparametric cardiovascular magnetic resonance (CMR) for detecting cardiac allograft vasculopathy (CAV) using contemporary invasive epicardial artery and microvascular assessment techniques as reference standards, and to compare the performance of CMR with that of angiography. CAV continues to limit the long-term survival of heart transplant recipients. Coronary angiography has a class I recommendation for CAV surveillance and annual or biannual surveillance angiography is performed routinely in most centers. All transplant recipients referred for surveillance angiography at a single UK center over a 2-year period were prospectively screened for study eligibility. Patients prospectively underwent coronary angiography followed by coronary intravascular ultrasound, fractional flow reserve and index of microcirculatory resistance. Within one month patients underwent multiparametric CMR, including assessment of regional and global ventricular function, absolute myocardial blood flow quantification and myocardial tissue characterization. In addition, 10 healthy volunteers underwent CMR. Forty-eight patients were recruited; median 7.1 years (IQR 4.6-10.3) since transplantation. CMR myocardial perfusion reserve was the only independent predictor of both epicardial (β = -0.57, p<0.001) and microvascular disease (β = -0.60, p<0.001) on stepwise multivariable regression. CMR myocardial perfusion reserve significantly outperformed angiography for detecting moderate CAV (AUC 0.89 (0.79-1.0) v 0.59 (0.42-0.77), p=0.01) and severe CAV (AUC 0.88 (0.78-0.98) v 0.67 (0.52-0.82), p=0.05). CAV, including epicardial and microvascular components, can be detected more accurately using non-invasive CMR-based absolute myocardial blood flow assessment than with invasive coronary angiography, the current clinical surveillance technique.
    Journal of the American College of Cardiology 12/2013; · 14.09 Impact Factor
  • Circulation Cardiovascular Imaging 07/2013; 6(4):e26-7. · 5.80 Impact Factor
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    Journal of Cardiovascular Magnetic Resonance 05/2013; 15(1). · 4.44 Impact Factor
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    ABSTRACT: BACKGROUND: -Extracellular matrix expansion is a key element of ventricular remodeling and a potential therapeutic target. Cardiovascular magnetic resonance (CMR) T1-mapping techniques are increasingly used to evaluate myocardial extracellular volume (ECV), however the most widely applied methods are without histological validation. Our aim was to perform comprehensive validation of; A, dynamic-equilibrium CMR (DynEq-CMR), where ECV is quantified using hematocrit-adjusted myocardial and blood T1 values measured before and after gadolinium bolus; and B, isolated measurement of myocardial T1, used as an ECV surrogate. METHODS AND RESULTS: -Whole-heart histological validation was performed using 96 tissue samples, analyzed for picrosirius red collagen volume fraction (CVF), obtained from each of 16-segments of the explanted hearts of 6 patients undergoing heart transplantation who had prospectively undergone CMR prior to transplantation (median interval between CMR and transplantation 29 days). DynEq-CMR-derived ECV was calculated from T1 measurements made using a modified look locker inversion recovery sequence before and 10- and 15-minutes post-contrast. In addition, ECV was measured 2-20 minutes post-contrast in 30 healthy volunteers. There was a strong linear relationship between DynEq-CMR-derived ECV and histological CVF (p<0.001; within-subject r=0.745, p<0.001; r(2)=0.555; between-subject r=0.945, p<0.01, r(2)=0.893; for ECV calculated using 15-minute post-contrast T1). Correlation was maintained throughout the entire heart. Isolated post-contrast T1 measurement showed significant within-subject correlation with histological CVF (r=-0.741, p<0.001; r(2)=0.550 for 15 minute post-contrast T1), but between-subject correlations were not significant. DynEq-CMR-derived ECV varied significantly according to contrast dose, myocardial region and gender. CONCLUSIONS: -DynEq-CMR-derived ECV shows a good correlation with histological CVF throughout the whole heart. Isolated post-contrast T1 measurement is insufficient for ECV assessment.
    Circulation Cardiovascular Imaging 04/2013; · 5.80 Impact Factor
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    ABSTRACT: Heart transplantation (HTX) is the gold standard surgical treatment for patients with advanced heart failure. The prevalence of hepatitis B and hepatitis C infection in HTX recipients is over 10%. Despite its increased prevalence, the long-term outcome in this cohort is still not clear. There is a reluctance to place these patients on transplant waiting list given the increased incidence of viral reactivation and chronic liver disease after transplant. The emergence of new antiviral therapies to treat this cohort seems promising but their long-term outcome is yet to be established. The aim of this paper is to review the literature and explore whether it is justifiable to list advanced heart failure patients with coexistent hepatitis B/C infection for HTX.
    Journal of Transplantation 01/2013; 2013:748578.
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    ABSTRACT: Despite modern immunosuppressive regimes, acute rejection remains a leading cause of morbidity and mortality in heart transplant recipients. Clinical features are unreliable, and therefore, screening is performed in order to detect rejection, and hence, augment immunosuppressive therapy, at an early stage, with the aim of reducing short- and long-term sequelae. Histological analysis of right ventricular myocardial tissue obtained at endomyocardial biopsy remains the 'gold standard' surveillance technique; however 'biopsy-negative' rejection occurs in up to 20% of patients, the procedure is associated with uncommon but potentially serious complications and it is expensive. Non-invasive screening would, conceivably, be safer, more tolerable and cheaper, and could potentially allow more comprehensive monitoring. The evidence for non-invasive methods of diagnosing acute rejection, including assessment of myocardial deformation, myocardial tissue characterisation, electrophysiological monitoring, visualisation of cellular and molecular components of rejection and peripheral monitoring of immune activation, is reviewed.
    Heart (British Cardiac Society) 12/2012; · 5.01 Impact Factor
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    ABSTRACT: Increased resting heart rate is an independent modifiable risk factor for the development of cardiovascular disease. Numerous studies have demonstrated improved clinical outcomes with heart rate reduction in patients with coronary artery disease and heart failure, but its role in transplanted hearts is not yet established. Sinus tachycardia is more common in heart transplant recipients due to graft denervation. Although a large number of studies have recognized increased heart rate as a predictor of native coronary artery atherosclerosis and overall cardiac mortality, contradicting results have been observed in heart transplant recipients. There is no clear consensus about what the normal range of heart rate should be following heart transplantation. The aim of this article was to review the literature to evaluate whether heart rate reduction should be considered in heart transplant recipients. Dr. Simon G. Williams and Dr. Steven M. Shaw have received honoraria from Servier for advisory work. The authors have no other funding, financial relationships, or conflicts of interest to disclose.
    Clinical Cardiology 08/2012; · 1.83 Impact Factor
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    ABSTRACT: The functional importance of protein-protein interactions indicates that there should be strong evolutionary constraint on their interaction interfaces. However, binding interfaces are frequently affected by amino acid replacements. Change due to coevolution within interfaces can contribute to variability but is not ubiquitous. An alternative explanation for the ability of surfaces to accept replacements may be that many residues can be changed without affecting the interaction. Candidates for these types of residues are those that make interchain interaction only through the protein main chain, β-carbon, or associated hydrogen atoms. Since almost all residues have these atoms, we hypothesize that this subset of interface residues may be more easily substituted than those that make interactions through other atoms. We term such interactions "residue type independent." Investigating this hypothesis, we find that nearly a quarter of residues in protein interaction interfaces make exclusively interchain residue-type-independent contacts. These residues are less structurally constrained and less conserved than residues making residue-type-specific interactions. We propose that residue-type-independent interactions allow substitutions in binding interfaces while the specificity of binding is maintained.
    Journal of Molecular Biology 04/2012; 419(5):387-96. · 3.91 Impact Factor
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    ABSTRACT: Brain natriuretic peptide (BNP) remains elevated after cardiac transplantation despite replacement of the failing ventricle. Serum peaks are also seen during acute rejection episodes independent of intracardiac hemodynamic disturbance. High BNP levels are also reported during bacterial sepsis, burns, stroke and myocardial infarction. Given all of these conditions are linked by immune activation processes, we hypothesised that BNP is an immunoactive agent. Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood of 40 cardiac transplant recipients. Cells were co-cultured for 72h in the presence or absence of BNP. Cells were then immunophenotyped using flow cytometry. Cell death pathways were determined using caspase 3 quantification and mitochondrial membrane assessment. Supernatants were analysed for cytokine, chemokine and growth factor production using luminex. Co-culture of CD8+ T cells with BNP reduced cell number, and increased intracellular caspase 3. Supernatant analysis revealed that BNP reduced the expression of inflammatory cytokines including TNF-α, IL-1α and IL-6. However it preserved the production of anti-inflammatory and regulatory cytokines such as IL-4, 5 and 13. Our findings provide evidence that BNP directly induces CD8+ T cell apoptosis via a caspase 3 associated mechanism from cardiac transplant patients. This may impart significant consequences on immune mediated disease processes, such as allograft rejection.
    Transplant Immunology 11/2011; 26(2-3):119-22. · 1.52 Impact Factor
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    ABSTRACT: Background / Purpose: The aim of this work was to identify specificity determinants for yeast protein-protein interactions.The hypothesis was that interacting residues contributing to specificity would be more conserved than others. Main conclusion: The main conclusion is that some residues contribute more to the specificity of the interaction and are more conserved, whereas other variable residues would contribute to the interaction energy or make opportunistic bonds.
    ISMB/ECCB 2011; 09/2011
  • Circulation Cardiovascular Imaging 09/2011; 4(5):583-93. · 5.80 Impact Factor
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    ABSTRACT: The high levels of sequence diversity and rapid rates of evolution of HIV-1 represent the main challenges for developing effective therapies. However, there are constraints imposed by the three-dimensional protein structure that affect the sequence space accessible to the evolution of HIV-1. Here, we present a strategy for predicting the set of possible amino acid replacements in HIV. Our approach is based on the identification of likely amino acid changes in the context of these structural constraints using environment-specific substitution matrices as well as considering the physical constraints imposed by local structure. Assessment of the power of various published algorithms in predicting the evolution of HIV-1 Gag P17 shows that it is possible to use these methods to make accurate predictions of the sequence diversity. Our own method, SubFit, uses knowledge of local structural constraints; it achieves similar prediction success with the best-performing methods. We also show that erroneous predictions are largely due to infrequently occurring amino acids that will probably have severe fitness costs for the protein. Future improvements; for example, incorporating covariation and immunological constraints will permit more reliable prediction of viral evolution.
    Journal of Molecular Biology 07/2011; 410(5):1023-34. · 3.91 Impact Factor
  • Parminder S Chaggar, Steven M Shaw, Simon G Williams
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    ABSTRACT: Severe mental illnesses, such as schizophrenia and bipolar affective disorder, are associated with excess cardiovascular morbidity and mortality. Cardiovascular risk in psychiatric disorders is partly related to antipsychotic therapy, especially second-generation or atypical antipsychotics. Some antipsychotic medications are associated with proatherogenic conditions including insulin resistance and dyslipidemia. In particular, olanzapine and clozapine have been consistently demonstrated to promote insulin resistance and dyslipidemia. Ziprasidone and amisulpiride may be associated with more favorable metabolic effects. Many of the published data relating to metabolic effects of anti-psychotics originate from retrospective studies. However, prospective randomized-controlled data are emerging, and the latest evidence is described here.
    The Journal of Clinical Pharmacology 05/2011; 51(5):631-8. · 2.84 Impact Factor
  • British journal of hospital medicine (London, England: 2005) 01/2011; 72(1):50-1. · 0.25 Impact Factor
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    ABSTRACT: A link between diabetes mellitus (DM) and heart failure (HF) has been well-recognized for more than a century. HF is also closely linked to abnormal glucose regulation (AGR) and insulin resistance (IR) in patients without DM and, similarly, these conditions commonly coexist. In epidemiological studies, each condition appears to predict the other. The prevalence of AGR/IR in HF patients without DM is significantly underrecognized and, as yet, the optimal method for screening for these abnormalities in the outpatient setting is unclear. The purpose of this review is to overview the prevalence and prognostic impact of AGR and IR in HF patients without DM and discuss potential pathophysiological pathways that link these conditions with HF. The severity of glucose intolerance in patients with HF correlates with functional and clinical severity of HF and is an independent predictor of an adverse outcome. It is thought that changes in cardiac metabolism, including a switch from glucose metabolism toward fatty acid metabolism, may in part contribute to the pathophysiological processes associated with HF patients with AGR/IR. We discuss how pharmacological targeting of metabolic pathways in the myocardium of these patients with HF may represent novel therapeutic strategies in these at-risk patients.
    Journal of cardiac failure 09/2010; 16(9):761-8. · 3.25 Impact Factor
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    Osman Najam, Nizar Yonan, Simon G Williams, Steven M Shaw
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    ABSTRACT: Following cardiac transplantation, registry data has demonstrated a gradual improvement in survival over the last several decades, which is testament to continual improvement in aftercare strategy. However, a significant number of patients will eventually develop a new syndrome of chronic heart failure, owing to the multitude of physiological processes that occur after transplantation. This condition, referred to as chronic graft failure (CGF) should be regarded as a unique illness rather than one that is simply analogous with chronic heart failure. In particular, the unique pathophysiological (and pharmacological) environment in the setting of CGF presents a challenging situation to the transplant physician. There is uncertainty over which treatments to offer given a paucity of clinical trial data to support the use of standard heart failure treatments in CGF. In this review, we discuss which chronic heart failure treatments could be considered in the setting of CGF based on their mechanisms of action, benefits within the native heart failure setting, and the relevant issues within the posttransplant environment.
    Cardiovascular Therapeutics 01/2010; 28(1):48-58. · 2.85 Impact Factor
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    ABSTRACT: Advances in medicine continue to drive forward through the practice of often impressive and innovative investigation. Through the application of randomized clinical trials, statistical analyses deliver the notorious "P values" to provide evidence of whether an intervention results in the desired clinical effect. However, it would appear that it is becoming increasingly common for trial reports to "cheat" the statistical system, particularly when lucrative industrial reward might be at stake. Fortunately, there is a safety net in place for the clinician who is less well accustomed to critiquing the research manuscript. In the United States, the Food and Drug Administration rigorously analyzes evidence relating to safety and efficacy of new therapies before approving them for general use. In Europe, the European Medicines Agency provides a similar service. Yet of much concern, there appears to be clear differences over the respective level of scrutiny of clinical trial data. This article discusses the unease of how a flawed international trial report appeared to deceive the European Union into approving a device-based product for chronic heart failure despite an important lack of credible data.
    American heart journal 09/2009; 158(2):149-51. · 4.65 Impact Factor
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    Journal of cardiac failure 09/2009; 15(6):549; author reply 549-51. · 3.25 Impact Factor