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ObjectiveIdentification of patients at risk of adverse outcome from heart failure (HF) at an early stage is a priority. Growth differentiation factor (GDF)-15 has emerged as a potentially useful biomarker. This study sought to identify determinants of circulating GDF-15 and evaluate its prognostic value, in patients at risk of HF or with HF but before first hospitalisation.MethodsProspective, longitudinal cohort study of 2166 consecutive patients in stage A–C HF undergoing cardiovascular magnetic resonance and measurement of GDF-15. Multivariable linear regression investigated determinants of GDF-15. Cox proportional hazards modelling, Net Reclassification Improvement and decision curve analysis examined its incremental prognostic value. Primary outcome was a composite of first hospitalisation for HF or all-cause mortality. Median follow-up was 1093 (939–1231) days.ResultsMajor determinants of GDF-15 were age, diabetes and N-terminal pro-B-type natriuretic peptide, although despite extensive phenotyping, only around half of the variability of GDF-15 could be explained (R20.51). Log-transformed GDF-15 was the strongest predictor of outcome (HR 2.12, 95% CI 1.71 to 2.63) and resulted in a risk prediction model with higher predictive accuracy (continuous Net Reclassification Improvement 0.26; 95% CI 0.13 to 0.39) and with greater clinical net benefit across the entire range of threshold probabilities.ConclusionIn patients at risk of HF, or with HF but before first hospitalisation, GDF-15 provides unique information and is highly predictive of hospitalisation for HF or all-cause mortality, leading to more accurate risk stratification that can improve clinical decision making.Trial registration numberNCT02326324.

Myocardial fibrosis, measured using magnetic resonance extracellular volume (ECV), associates with adverse outcome in heart failure with preserved ejection fraction (HFpEF). In the PIROUETTE (The Pirfenidone in Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction) trial, the novel anti-fibrotic agent pirfenidone reduced myocardial fibrosis. We sought to identify baseline characteristics that associate with myocardial fibrotic burden, the change in myocardial fibrosis over a year, and predict response to pirfenidone in patients with HFpEF. Amongst patients enrolled in the PIROUETTE trial (n = 107), linear regression models were used to assess the relationship between baseline variables and baseline myocardial ECV, with change in myocardial ECV adjusting for treatment allocation, and to identify variables that modified the pirfenidone treatment effect. Body mass index, left atrial reservoir strain, haemoglobin and aortic distensibility were associated with baseline ECV in stepwise modelling, and systolic blood pressure, and log N-terminal pro B-type natriuretic peptide were associated with baseline ECV in clinically-guided modelling. QRS duration, left ventricular mass and presence of an infarct at baseline were associated with an increase in ECV from baseline to week 52. Whilst QRS duration, presence of an infarct, global longitudinal strain and left atrial strain modified the treatment effect of pirfenidone when considered individually, no variable modified treatment effect on multivariable modelling. Baseline characteristics were identified that associate with myocardial fibrosis and predict change in myocardial fibrosis. No variables that independently modify the treatment effect of pirfenidone were identified (PIROUETTE, NCT02932566).

Identifying people who are at risk of being admitted to hospital (hospitalised) for heart failure and death, and particularly those who have not previously been hospitalised for heart failure, is a priority. We aimed to develop and externally validate a prognostic model involving contemporary deep phenotyping that can be used to generate individual risk estimates of hospitalisation for heart failure or all-cause mortality in patients with, or at risk of, heart failure, but who have not previously been hospitalised for heart failure.

Heart failure (HF) most commonly occurs in patients who have had a myocardial infarction (MI), but factors other than MI size may be deterministic. Fibrosis of myocardium remote from the MI is associated with adverse remodeling. We aimed to 1) investigate the association between remote myocardial fibrosis, measured using cardiovascular magnetic resonance (CMR) extracellular volume fraction (ECV), and HF and death following MI, 2) identify predictors of remote myocardial fibrosis in patients with evidence of MI and determine the relationship with infarct size.

In heart failure with preserved ejection fraction (HFpEF), the occurrence of myocardial fibrosis is associated with adverse outcome. Whether pirfenidone, an oral antifibrotic agent without hemodynamic effect, is efficacious and safe for the treatment of HFpEF is unknown. In this double-blind, phase 2 trial (NCT02932566), we enrolled patients with heart failure, an ejection fraction of 45% or higher and elevated levels of natriuretic peptides. Eligible patients underwent cardiovascular magnetic resonance and those with evidence of myocardial fibrosis, defined as a myocardial extracellular volume of 27% or greater, were randomly assigned to receive pirfenidone or placebo for 52 weeks. Forty-seven patients were randomized to each of the pirfenidone and placebo groups. The primary outcome was change in myocardial extracellular volume, from baseline to 52 weeks. In comparison to placebo, pirfenidone reduced myocardial extracellular volume (between-group difference, −1.21%; 95% confidence interval, −2.12 to −0.31; P= 0.009), meeting the predefined primary outcome. Twelve patients (26%) in the pirfenidone group and 14 patients (30%) in the placebo group experienced one or more serious adverse events. The most common adverse events in the pirfenidone group were nausea, insomnia and rash. In conclusion, among patients with HFpEF and myocardial fibrosis, administration of pirfenidone for 52 weeks reduced myocardial fibrosis. The favorable effects of pirfenidone in patients with HFpEF will need to be confirmed in future trials.

Chronic viral infections represent a unique challenge to the infected host. Persistently replicating viruses outcompete or subvert the initial antiviral response, allowing the establishment of chronic infections that result in continuous stimulation of both the innate and adaptive immune compartments. This causes a profound reprogramming of the host immune system, including attenuation and persistent low levels of type I interferons, progressive loss (or exhaustion) of CD8+T cell functions, and specialization of CD4+T cells to produce interleukin-21 and promote antibody-mediated immunity and immune regulation. Epigenetic, transcriptional, posttranscriptional, and metabolic changes underlie this adaptation or recalibration of immune cells to the emerging new environment in order to strike an often imperfect balance between the host and the infectious pathogen. In this review we discuss the common immunological hallmarks observed across a range of different persistently replicating viruses and host species, the underlying molecular mechanisms, and the biological and clinical implications.

The risk of graft failure is the pivotal measure of effectiveness when evaluating immunosuppressive regimens for renal transplantation. However, to date most randomized trials of immunosuppressive therapy have had acute rejection as the primary endpoint for treatment comparisons. The objective here was to review the evidence relating acute rejection to renal graft function and graft survival.

IntroductionMany conditions considered to be primary lung diseases are independently associated with adverse cardiovascular outcome. Systemic inflammation and subsequent fibrosis are hypothesised mechanisms. However, beyond the mechanical impact on right heart, characterisation of myocardial involvement in lung disease remains limited.We present a combined heart-lung MRI protocol which allows simultaneous interrogation of heart and lung structure and function.MethodsProtocol (1.5T Siemens Avanto) includes steady state free precession (SSFP) cine imaging of the heart (standard long and short axis views), followed by inspiration and expiration cine lung imaging (sagittal planes). T2 prepared SFFP and T1 MOLLIE images are acquired in standard cardiac planes and left and right lungs.Dynamic contrast enhanced MRI (DCE-MRI) sequences are performed using free breathing 2D saturation-recovery FLASH dynamic acquisitions in four planes (two LV short axis slices, left and right lung sagittal slices) with temporal resolution equal to 50% of patient’s heart rate. Three boluses of gadolinium contrast (dotarem) are administered: 0.005 mmol/kg, followed by 2 min of dynamic acquisitions; 0.05 mmol/kg followed by 6 min of dynamics; final dose of 0.1 mmol/kg.Finally, late enhancement imaging and post-contrast T1 mapping are performed. Overall each scan protocol lasted for approximately 60 min.ResultsParametric mapping and LGE imaging provides direct tissue characterisation.Myocardial and lung contrast agent kinetics are modelled from the DCE images in matlab (Extended Kety Model) to determine heart and lung capillary permeability (Ktrans), extracellular volume (ECV) and plasma volume fraction (vp). Regions of interest are drawn in the LV and RV cavities to obtain arterial input functions (AIF). The low dose AIF is multiplied by a factor of ten and the first pass peak is combined with the high dose AIF curve in order to correct for saturation effects (Figure 1).Examples of ECV maps are shown in Figure 2 and 3.ConclusionsThis combined heart lung protocol is an efficient and comprehensive imaging tool for simultaneous myocardial and pulmonary assessment. It has a potential to help elucidate complex links between pulmonary and myocardial pathologies, and is a model for other dual organ parametric MR imaging.[Figure][Figure][Figure]

AimsInvestigators have proposed that cardiovascular magnetic resonance (CMR) should have restrictions similar to those of ionising imaging techniques due to proposed alterations to leukocytes. We aimed to investigate the acute effect of CMR on leukocyte DNA integrity and cell viability in vitro, and in a large cohort of patients in vivo.Methods and resultsIn vitrostudy: Peripheral blood mononuclear cells (PBMC) were isolated from healthy volunteers and assessed: 1) immediately following PBMC isolation, 2) after standing on the benchside as a temperature and time control, 3) after a standard CMR scan. Histone H2AX phosphorylation (γ-H2AX), an indicator of DNA damage, and leukocyte counts were quantified using flow cytometry. In vivostudy: Blood samples were taken from 64 consecutive consenting patients immediately before and after a standard clinical scan. Samples were analysed for T cell count and γ-H2AX expression.CMR scanning was associated with a significant increase in leukocyte γ-H2AX expression, indicating DNA damage occurs. We also observed a trend towards a significant decrease in absolute leukocyte numbers in vitrofollowing CMR. CMR was not associated with a significant change in γ-H2AX expression in vivo, although there were significant inter-patient variations. There was a significant reduction in circulating T cells following CMR.ConclusionCMR was not associated with DNA damage in vivo. γ-H2AX expression varied markedly between individuals, therefore small studies using γ-H2AX as a marker of DNA damage should be interpreted with caution. CMR was associated with a statistically significant reduction in viable leukocytes, although the clinical relevance of the magnitude is unclear. Further work is warranted to contextualise these findings and delineate their impact.

IntroductionQuantification of active myocardial inflammation may improve diagnosis, guide management and provide trial end-points for novel therapies. Ultrasmall particles of iron oxide (USPIO) are phagocytosed by activated leukocytes and USPIO-enhanced CMR is increasingly used to assess tissue inflammation. We aimed to; 1. Compare T2* imaging with T1 mapping, which is proposed as an alternative for ‘native’ cardiac iron measurement; 2. Determine whether imaging at a single time point post-USPIO is sufficient to detect active accumulation in tissue; 3. Determine whether USPIO signal from infarct and remote zones in acute myocardial infarction (MI) reflects active myocardial accumulation or passive ‘wash-through’ in oedematous myocardium.MethodsFour healthy volunteers and six patients with acute MI underwent 1.5T CMR, including T1 and T2* mapping, before and at multiple time points following 4 mg/kg ferumoxytol.ResultsNormalised T2* of spleen, an organ with high active leukocyte activity, dropped post-USPIO and remained low over the study period (Figure 1), with no correlation seen between spleen T2* and blood T1 (rho=−0.43, p=0.875). In comparison, T1 recovery in spleen correlated strongly with T1 recovery in blood (rho=0.924, p<0.001). In healthy myocardium, an organ with low leukocyte activity, T1 and T2*recovery both correlated strongly with blood T1 (rho=0.953, p<0.001; rho=0.935, p<0.001 respectively).In MI, absolute T2* values dropped and remained significantly lower in infarcted (15 vs 27ms, p<0.001, 22 vs 38 ms, p=0.001) and remote myocardium (21 vs 27ms, p=0.05, 28 vs 38 ms, p=0.024) compared to healthy controls. T2* and T1 recovery curves post-USPIO were significantly different in both infarcted (p=0.028) and remote myocardium (p=0.004; Figures 2).Conclusions0T2* is sensitive to active tissue accumulation of USPIO, likely because T2* reflects field gradients, such as those generated by compartmentalised (phagocytosed) USPIO. T1, which is due to short range dipolar interactions that reduce as USPIOs wash-out, simply tracks passive wash-through. T1 is therefore less suitable for detecting active leukocytes. Measuring T2* at a single time point post-USPIO is insufficient to determine tissue accumulation from passive wash-through. USPIO signal from infarct and remote zones in acute MI appears to genuinely reflect active myocardial accumulation, presumably due to phagocytosis by activated leukocytes.[Figure][Figure]

Several letters to the editor are presented in response to the articles "Who Let the Toffs Out?" by Stuart Maconie, "Battle of the Tax Bands," by Alan Milburn, and "Real Meals," by Will Self, published in the January 30, 2015 issue.

Introduction:This analysis assesses whether Rituximab added to a Fludarabine Cyclophosphamide regimen (R-FC) is a cost-effective first-line treatment option for previously untreated CLL patients, using evidence from the phase III randomised controlled trial, ML17102 (CLL8) (Hallek et al., ASH 2008). In this trial, R-FC significantly prolonged the primary endpoint of progression–free survival (PFS) compared to FC alone and was well tolerated with no unexpected safety signals.

Introduction: This analysis assesses whether Rituximab added to a Fludarabine Cyclophosphamide regimen (R-FC) is a cost-effective first-line treatment option for previously untreated CLL patients, using evidence from the phase III randomised controlled trial, ML17102 (CLL8) (Hallek et al., ASH 2008). In this trial, R-FC significantly prolonged the primary endpoint of progression–free survival (PFS) compared to FC alone and was well tolerated with no unexpected safety signals. Methods: A cost-effectiveness model was developed to evaluate the life-time health outcomes and direct costs of R-FC compared to FC as first-line treatment for CLL patients in the UK. Patients were modelled to be in one of three health states; PFS, Progressed or Death. The best parametric fit (Weibull) was used to extrapolate PFS beyond the end of the CLL8 trial follow-up period to a 15 year life-time horizon. The number of patients in each treatment arm that died while in PFS was based on the maximum of either the observed rate of death or background mortality. Because median overall survival had not been reached in CLL-8, a Markov process was used to model the transition from the progressed health state to death. Given the non significant difference in post progression survival by treatment (R-FC or FC), patients transitioning from progression to death were modelled as a single population with mean time to death (Kaplan-Meier) converted to a monthly probability of dying. This approach is conservative in that treatment benefit is exclusively a function of time spent in PFS. This Markovian approach is conservative in that treatment benefit is exclusively a function of time spent in PFS. Predicted time in each health state was weighted using CLL utility scores (Hancock et. al. 2002) to account for patient quality of life and estimate the Quality Adjusted Life Years (QALYs). Drug administration, patient monitoring and pharmacy costs were taken from the NHS schedule of reference costs 2006 and the published literature. Blood transfusions, bone marrow transplants, stem cell therapy and second line CLL treatments collected prospectively in CLL8 were included in monitoring costs. The cost of treatment related grade 3 or 4 infections were not included in the analysis as the incidence between the two treatment arms was comparable (Hallek et al., ASH 2008). Both costs and outcomes were discounted by 3.5%. RESULTS: R-FC improves mean life expectancy by 1.33 years compared to FC alone. After adjusting for quality of life, the incremental quality-adjusted life expectancy estimated was 1.06 years. Improvements in health outcomes were attributed to an increase in the time R-FC patients spent in the PFS health state (1.17 years).Total direct costs were higher for R-FC by £13,081 per patient, however, this was partially offset by a reduction in medication and monitoring costs incurred in the progressed health state. The incremental cost-effectiveness ratios (ICERs) were estimated to be £9558 per Life Year Gained with R-FC. When health-related quality of life was taken into account, the ICER was £12,387 per QALY gained for R-FC, well below commonly accepted thresholds in the UK. Although there is uncertainty associated with the progression of CLL and relapse treatment costs, the ICER did not exceed £22,458 per QALY despite a wide variation in each parameter value used in the probabilistic sensitivity analysis. CONCLUSIONS: Based on the significant prolongation of PFS demonstrated in CLL8, first-line R-FC substantially increases quality-adjusted life expectancy for CLL patients and is well within the UK threshold of cost-effectiveness. The sensitivity analysis provides adequate reassurance that the cost-effectiveness of R-FC held under most plausible scenarios.

Objectives: Both ASCT and R-Maint have been shown to be effective therapies for treating rituximab naïve patients with relapsed/refractory follicular lymphoma. The aim of this research was to assess the cost effectiveness of ASCT compared to R-Maint in this patient population (following a response to chemotherapy induction) from a UK perspective.