High-Sensitivity Cardiac Troponin and New-Onset Heart Failure: Could a Quantitative Meta-Analysis Be Performed for the C Index?

I have read the article by Evans and colleagues published in the JACC – Heart Failure with a great interest. The authors conducted a systematic review and meta-analysis of 67,063 patients with 4,165 incident heart failure events from 16 prospective studies. The results in this study suggest that serum high-sensitivity cardiac Troponin is strongly associated with the risk for incident heart failure beyond conventional risk factors. Certainly, Evans et al. have conducted a very valuable and exciting study. However, the authors mentioned that they were not able to perform a quantitative meta-analysis of the C index data in this study because some studies did not report confidence intervals (CI) for C indexes and their changes. Could the authors calculate a quantitative meta-analysis of the C index only using fully reported studies? This would provide a clearer view that many readers might be interested

Amyloidosis in the Era of Mass Spectrometry-Based Proteomics

I read the paper by Kotecha et al. with great interest. Certainly, the authors conducted a very valuable and exciting study for which 286 patients were recruited, including 100 with systemic light-chain amyloidosis and 163 with cardiac transthyretin amyloidosis. The findings in this study by histology and cardiovascular magnetic resonance T2 mapping suggest that myocardial edema is a mechanism additional to amyloid infiltration in contributing to prognosis in amyloidosi

Immunosuppression Does Not Reduce Antitumor Efficacy

I read with great interest the paper by Mahmood et al. The authors conducted a very valuable and interesting study of 35 patients with immune checkpoint inhibitor (ICI)-associated myocarditis compared with 105 ICI-treated patients without myocarditis in a multicenter registry with 8 sites. The study found that myocarditis developed at a median of 34 days in patients receiving ICIs for the treatment of cancer. Moreover, the authors indicated that there were higher serum troponin levels and major adverse cardiac event rates with the use of lower steroid doses; higher steroid doses were associated with lower serum troponin levels and major adverse cardiac event rates in ICI-treated patients with myocarditis

What is the added value of the waist-to-hip ratio on top of the BIOSTAT risk prediction model in patients with heart failure?

I read with great interest the article by Streng et al. published in the European Journal of Heart Failure. I congratulate the authors for a solid study design and very exciting results. Streng et al. conducted a very valuable study where 1479 patients with waist and hip measurements from the BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT‐CHF) validation cohort were analysed. The authors found that there was a significant association between waist‐to‐hip ratio (WHR) and mortality in women with heart failure (HF)

The Edge Effect in High-Throughput Proteomics: A Cautionary Tale

In order for mass spectrometry to continue to grow as a platform for high-throughput clinical and translational research, careful consideration must be given to quality control by ensuring that the assay performs reproducibly and accurately and precisely. In particular, the throughput required for large cohort clinical validation in biomarker discovery and diagnostic screening has driven the growth of multiplexed targeted liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) assays paired with sample preparation and analysis in multiwell plates. However, large scale MS-based proteomics studies are often plagued by batch effects: sources of technical variation in the data, which can arise from a diverse array of sources such as sample preparation batches, different reagent lots, or indeed MS signal drift. These batch effects can confound the detection of true signal differences, resulting in incorrect conclusions being drawn about significant biological effects or lack thereof. Here, we present an intraplate batch effect termed the edge effect arising from temperature gradients in multiwell plates, commonly reported in preclinical cell culture studies but not yet reported in a clinical proteomics setting. We present methods herein to ameliorate the phenomenon including proper assessment of heating techniques for multiwell plates and incorporation of surrogate standards, which can normalize for intraplate variation

Modulation of EGFR Activity by Molecularly Imprinted Polymer Nanoparticles Targeting Intracellular Epitopes

In recent years, molecularly imprinted polymer nanoparticles (nanoMIPs) have proven to be an attractive alternative to antibodies in diagnostic and therapeutic applications. However, several key questions remain: how suitable are intracellular epitopes as targets for nanoMIP binding? And to what extent can protein function be modulated via targeting specific epitopes? To investigate this, three extracellular and three intracellular epitopes of epidermal growth factor receptor (EGFR) were used as templates for the synthesis of nanoMIPs which were then used to treat cancer cells with different expression levels of EGFR. It was observed that nanoMIPs imprinted with epitopes from the intracellular kinase domain and the extracellular ligand binding domain of EGFR caused cells to form large foci of EGFR sequestered away from the cell surface, caused a reduction in autophosphorylation, and demonstrated effects on cell viability. Collectively, this suggests that intracellular domain-targeting nanoMIPs can be a potential new tool for cancer therapy

Circulating sphingolipids and relationship to cardiac remodelling before and following a low-energy diet in asymptomatic Type 2 Diabetes

Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogenous multi-system syndrome with limited efficacious treatment options. The prevalence of Type 2 diabetes (T2D) continues to rise and predisposes patients to HFpEF, and HFpEF remains one of the biggest challenges in cardiovascular medicine today. Novel therapeutic targets are required to meet this important clinical need. Deep phenotyping studies including -OMIC analyses can provide important pathogenic information to aid the identification of such targets. The aims of this study were to determine; 1) the impact of a low-energy diet on plasma sphingolipid/ceramide profiles in people with T2D compared to healthy controls and, 2) if the change in sphingolipid/ceramide profile is associated with reverse cardiovascular remodelling. Methods: Post-hoc analysis of a randomised controlled trial (NCT02590822) including adults with T2D with no cardiovascular disease who completed a 12-week low-energy (∼810 kcal/day) meal-replacement plan (MRP) and matched healthy controls (HC). Echocardiography, cardiac MRI and a fasting blood for lipidomics were undertaken pre/post-intervention. Candidate biomarkers were identified from case–control comparison (fold change > 1.5 and statistical significance p < 0.05) and their response to the MRP reported. Association between change in biomarkers and change indices of cardiac remodelling were explored. Results: Twenty-four people with T2D (15 males, age 51.1 ± 5.7 years), and 25 HC (15 male, 48.3 ± 6.6 years) were included. Subjects with T2D had increased left ventricular (LV) mass:volume ratio (0.84 ± 0.13 vs. 0.70 ± 0.08, p < 0.001), increased systolic function but impaired diastolic function compared to HC. Twelve long-chain polyunsaturated sphingolipids, including four ceramides, were downregulated in subjects with T2D at baseline. Three sphingomyelin species and all ceramides were inversely associated with LV mass:volume. There was a significant increase in all species and shift towards HC following the MRP, however, none of these changes were associated with reverse cardiac remodelling. Conclusion: The lack of association between change in sphingolipids/ceramides and reverse cardiac remodelling following the MRP casts doubt on a causative role of sphingolipids/ceramides in the progression of heart failure in T2D. Trial registration: NCT02590822

Proenkephalin and prognosis in heart failure with preserved ejection fraction: a GREAT network study.

BACKGROUND: Proenkephalin (PENK), a stable endogenous opioid biomarker related to renal function, has prognostic utility in acute and chronic heart failure. We investigated the prognostic utility of PENK in heart failure with preserved ejection fraction (HFpEF), and its relationship to renal function, Body Mass Index (BMI), and imaging measures of diastolic dysfunction. METHODS: In this multicentre study, PENK was measured in 522 HFpEF patients (ejection fraction > 50%, 253 male, mean age 76.13 ± 10.73 years) and compared to 47 age and sex-matched controls. The primary endpoint was 2-years composite of all-cause mortality and/or heart failure rehospitalisation (HF). A subset (n = 163) received detailed imaging studies. RESULTS: PENK levels were raised in HFpEF (median [interquartile range] 88.9 [62.1-132.0]) compared to normal controls (56.3 [47.9-70.5]). PENK was correlated to urea, eGFR, Body Mass Index and E/e' (rs 0.635, - 0.741, - 0.275, 0.476, respectively, p < 0.0005). During 2 years follow-up 144 patients died and 220 had death/HF endpoints. Multivariable Cox regression models showed PENK independently predicted 2 year death/HF [hazard ratio (for 1 SD increment of log-transformed biomarker) HR 1.45 [95% CI 1.12-1.88, p = 0.005]], even after adjustment for troponin (HR 1.59 [1.14-2.20, p = 0.006]), and Body Mass Index (HR 1.63 [1.13-2.33, p = 0.009]). PENK showed no interaction with ejection fraction status for prediction of poor outcomes. Net reclassification analyses showed PENK significantly improved classification of death/HF outcomes for multivariable models containing natriuretic peptide, troponin and Body Mass Index (p < 0.05 for all). CONCLUSIONS: In HFpEF, PENK levels are related to BMI, and measures of diastolic dysfunction and are prognostic for all-cause mortality and heart failure rehospitalisation