A comprehensive characterization of the lipidome from limited starting material remains very challenging. Here we report a high-sensitivity lipidomics workflow based on nanoflow liquid chromatography ...and trapped ion mobility spectrometry (TIMS). Taking advantage of parallel accumulation-serial fragmentation (PASEF), we fragment on average 15 precursors in each of 100 ms TIMS scans, while maintaining the full mobility resolution of co-eluting isomers. The acquisition speed of over 100 Hz allows us to obtain MS/MS spectra of the vast majority of isotope patterns. Analyzing 1 µL of human plasma, PASEF increases the number of identified lipids more than three times over standard TIMS-MS/MS, achieving attomole sensitivity. Building on high intra- and inter-laboratory precision and accuracy of TIMS collisional cross sections (CCS), we compile 1856 lipid CCS values from plasma, liver and cancer cells. Our study establishes PASEF in lipid analysis and paves the way for sensitive, ion mobility-enhanced lipidomics in four dimensions.
Objectives This study evaluated the safety, efficacy, and effect of MitraClip treatment on symptoms and left ventricular (LV) remodeling in nonresponders to cardiac resynchronization therapy (CRT). ...Background Moderate to severe functional mitral regurgitation (FMR) frequently persists after CRT, contributing to reduced or no response to CRT. Percutaneous repair with the MitraClip has been proposed as an additional therapeutic option in select patients with significant FMR. Methods Fifty-one severely symptomatic CRT nonresponders with significant FMR (grade ≥2, 100%) underwent MitraClip treatment. Changes in New York Heart Association functional class, degree of FMR, LV ejection fraction (EF), and LV end-diastolic/end-systolic volumes (EDV/ESV) before and after (3, 6, and 12 months) MitraClip implantation were recorded. Mortality data, including cause of death, were collected. Results MC treatment was feasible in all patients (49% 1 clip, 46% 2 clips). There were 2 periprocedural deaths. Median follow-up was 14 months (25th to 75th percentile: 8 to 17 months). New York Heart Association functional class improved acutely at discharge (73%) and continued to improve progressively during follow-up (regression model, p < 0.001). The proportion of patients with significant residual FMR (grade ≥2) progressively decreased during follow-up (regression model, p < 0.001). Reverse LV remodeling and improved LVEF were detected at 6 months, with further improvement at 12 months (regression model, p = 0.001, p = 0.008, and p = 0.031 for ESV, EDV, and LVEF, respectively). Overall 30-day mortality was 4.2%. Overall mortality during follow-up was 19.9 per 100 person-years (95% confidence interval: 10.3 to 38.3). Nonsurvivors had more compromised clinical baseline conditions, longer QRS duration, and a more dilated heart. Conclusions FMR treatment with the MitraClip in CRT nonresponders was feasible, safe, and demonstrated improved functional class, increased LVEF, and reduced ventricular volumes in about 70% of these study patients.
The utility of metabolomics is well documented; however, its full scientific promise has not yet been realized due to multiple technical challenges. These grand challenges include accurate chemical ...identification of all observable metabolites and the limiting depth-of-coverage of current metabolomics methods. Here, we report a combinatorial solution to aid in both grand challenges using UHPLC-trapped ion mobility spectrometry coupled to tandem mass spectrometry (UHPLC-TIMS-TOF-MS). TIMS offers additional depth-of-coverage through increased peak capacities realized with the multi-dimensional UHPLC-TIMS separations. Metabolite identification confidence is simultaneously enhanced by incorporating orthogonal collision cross section (CCS) data matching. To facilitate metabolite identifications, we created a CCS library of 146 plant natural products. This library was generated using TIMS with N
drift gas to record the
CCS
of plant natural products with a high degree of reproducibility; i.e., average RSD = 0.10%. The robustness of
CCS
data matching was tested using authentic standards spiked into complex plant extracts, and the precision of CCS measurements were determined to be independent of matrix affects. The utility of the UHPLC-TIMS-TOF-MS/MS in metabolomics was then demonstrated using extracts from the model legume
and metabolites were confidently identified based on retention time, accurate mass, molecular formula, and CCS.
Lipids play pivotal roles in an extensive range of metabolic and physiological processes. In recent years, the convergence of trapped ion mobility spectrometry and MS has enabled 4D-lipidomics, a ...highly promising technology for comprehensive lipid analysis. 4D-lipidomics assesses lipid annotations across four distinct dimensions—retention time, collisional cross section, m/z (mass-to-charge ratio), and MS/MS spectra—providing a heightened level of confidence in lipid annotation. These advantages prove particularly valuable when investigating complex disorders involving lipid metabolism, such as adrenoleukodystrophy (ALD). ALD is characterized by the accumulation of very-long-chain fatty acids (VLCFAs) due to pathogenic variants in the ABCD1 gene. A comprehensive 4D-lipidomics strategy of ALD fibroblasts demonstrated significant elevations of various lipids from multiple classes. This indicates that the changes observed in ALD are not confined to a single lipid class and likely impacts a broad spectrum of lipid-mediated physiological processes. Our findings highlight the incorporation of mainly saturated and monounsaturated VLCFA variants into a range of lipid classes, encompassing phosphatidylcholines, triacylglycerols, and cholesterol esters. These include ultra-long-chain fatty acids with a length of up to thirty carbon atoms. Lipid species containing C26:0 and C26:1 were the most frequently detected VLCFA lipids in our study. Furthermore, we report a panel of 121 new candidate biomarkers in fibroblasts, exhibiting significant differentiation between controls and individuals with ALD. In summary, this study demonstrates the capabilities of a 4D-lipid profiling workflow in unraveling novel insights into the intricate lipid modifications associated with metabolic disorders like ALD.
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Understanding of Alzheimer's disease (AD) pathophysiology requires molecular assessment of how key pathological factors, specifically amyloid β (Aβ) plaques, influence the surrounding ...microenvironment. Here, neuronal lipids have been implicated in Aβ plaque pathology, though the lipid microenvironment in direct proximity to Aβ plaques is still not fully resolved. A further challenge is the microenvironmental molecular heterogeneity, across structurally polymorphic Aβ features, such as diffuse, immature, and mature, fibrillary aggregates, whose resolution requires the integration of advanced, multimodal chemical imaging tools. Herein, we used matrix‐assisted laser desorption/ionization trapped ion mobility spectrometry time‐of‐flight based mass spectrometry imaging (MALDI TIMS TOF MSI) in combination with hyperspectral confocal microscopy to probe the lipidomic microenvironment associated with structural polymorphism of Aβ plaques in transgenic Alzheimer's disease mice (tgAPPSWE). Using on tissue and ex situ validation, TIMS MS/MS facilitated unambiguous identification of isobaric lipid species that showed plaque pathology‐associated localizations. Integrated multivariate imaging data analysis revealed multiple, Aβ plaque‐enriched lipid patterns for gangliosides (GM), phosphoinositols (PI), phosphoethanolamines (PE), and phosphatidic acids (PA). Conversely, sulfatides (ST), cardiolipins (CL), and polyunsaturated fatty acid (PUFA)‐conjugated phosphoserines (PS), and PE were depleted at plaques. Hyperspectral amyloid imaging further delineated the unique distribution of PA and PE species to mature plaque core regions, while PI, LPI, GM2 and GM3 lipids localized to immature Aβ aggregates present within the periphery of Aβ plaques. Finally, we followed AD pathology‐associated lipid changes over time, identifying plaque‐ growth and maturation to be characterized by peripheral accumulation of PI (18:0/22:6). Together, these data demonstrate the potential of multimodal imaging approaches to overcome limitations associated with conventional advanced MS imaging applications. This allowed for the differentiation of both distinct lipid components in a complex micro‐environment as well as their correlation to disease‐relevant amyloid plaque polymorphs.
Cover Image for this issue:
https://doi.org/10.1111/jnc.15390
Lipid species have long been implicated in Alzheimer’s disease pathology and beta‐amyloid (Aβ) plaque formation. Using trapped ion mobility spectrometry‐based mass spectrometry imaging (TIMS MSI) allowed us to resolve and unambiguously identify isobaric lipid species in situ that showed distinct localization patterns towards Aβ plaques. TIMS MSI was integrated with hyperspectral, confocal microscopy using conformation‐sensitive amyloid probes. Multivariate modeling of multimodal chemical imaging data identified lipid accumulations towards structurally distinct Aβ plaque pathology. These patterns were found to generally persist with progressing plaque pathology, while distinct polyunsaturated fatty acid‐conjugated phosphoinositol showed increased deposition with Aβ plaque maturation.
Cover Image for this issue:
https://doi.org/10.1111/jnc.15390
Biomarkers may help us to unravel differences in the underlying pathophysiology between heart failure (HF) patients with a reduced ejection fraction (HFrEF) and a preserved ejection fraction (HFpEF). ...Therefore, we compared biomarker profiles to characterize pathophysiological differences between patients with HFrEF and HFpEF.
We retrospectively analyzed 33 biomarkers from different pathophysiological domains (inflammation, oxidative stress, remodeling, cardiac stretch, angiogenesis, arteriosclerosis, and renal function) in 460 HF patients (21% HFpEF, left ventricular ejection fraction ≥45%) measured at discharge after hospitalization for acute HF. The association between these markers and the occurrence of all-cause mortality and/or HF-related rehospitalizations at 18 months was compared between patients with HFrEF and HFpEF. Patients were 70.6±11.4 years old and 37.4% were female. Patients with HFpEF were older, more often female, and had a higher systolic blood pressure. Levels of high-sensitive C-reactive protein were significantly higher in HFpEF, while levels of pro-atrial-type natriuretic peptide and N-terminal pro-brain natriuretic peptide were higher in HFrEF. Linear regression followed by network analyses revealed prominent inflammation and angiogenesis-associated interactions in HFpEF and mainly cardiac stretch-associated interactions in HFrEF. The angiogenesis-specific marker, neuropilin and the remodeling-specific marker, osteopontin were predictive for all-cause mortality and/or HF-related rehospitalizations at 18 months in HFpEF, but not in HFrEF (
for interaction <0.05).
In HFpEF, inflammation and angiogenesis-mediated interactions are predominantly observed, while stretch-mediated interactions are found in HFrEF. The remodeling marker osteopontin and the angiogenesis marker neuropilin predicted outcome in HFpEF, but not in HFrEF.
Abstract Objectives The authors sought to analyze height differences within the coronary artery tree in patients in a supine position and to quantify the impact of hydrostatic pressure on ...intracoronary pressure measurements in vitro. Background Although pressure equalization of the pressure sensor and the systemic pressure at the catheter tip is mandatory in intracoronary pressure measurements, subsequent measurements may be influenced by hydrostatic pressure related to the coronary anatomy in the supine position. Outlining and quantifying this phenomenon is important to interpret routine and pullback pressure measurements within the coronary tree. Methods Coronary anatomy was analyzed in computed tomography angiographies of 70 patients to calculate height differences between the catheter tip and different coronary segments in the supine position. Using a dynamic pressure simulator, the effect of the expected hydrostatic pressure resulting from such height differences on indices stenosis severity was assessed. Results In all patients, the left anterior and right posterior descending arteries are the highest points of the coronary tree with a mean height difference of −4.9 ± 1.6 cm and −3.8 ± 1.0 cm; whereas the circumflex artery and right posterolateral branches are the lowest points, with mean height differences of 3.9 ± 0.9 cm and 2.6 ± 1.6 cm compared with the according ostium. In vitro measurements demonstrated a correlation of the absolute pressure differences with height differences (r = 0.993; p < 0.0001) and the slope was 0.77 mm Hg/cm. The Pd/Pa ratio and instantaneous wave-free ratio correlated also with the height difference (fractional flow reserve r = 0.98; p < 0.0001; instantaneous wave-free ratio r = 0.97; p < 0.0001), but both were influenced by the systemic pressure level. Conclusions Hydrostatic pressure variations resulting from normal coronary anatomy in a supine position influence intracoronary pressure measurements and may affect their interpretation during stenosis severity assessment.
Sex differences in cardiomyopathies Meyer, Sven; van der Meer, Peter; van Tintelen, J. Peter ...
European journal of heart failure,
March 2014, Letnik:
16, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Cardiomyopathies are a heterogeneous group of heart muscle diseases with a variety of specific phenotypes. According to the contemporary European Society of Cardiology classification, they are ...classified into hypertrophic (HCM), dilated (DCM), arrhythmogenic right ventricular (ARVC), restrictive (RCM), and unclassified cardiomyopathies. Each class is aetiologically further categorized into inherited (familial) and non‐inherited (non‐familial) forms. There is substantial evidence that biological sex is a strong modulator of the clinical manifestation of these cardiomyopathies, and sex‐specific characteristics are detectable in all classes. For the clinician, it is important to know the sex‐specific aspects of clinical disease expression and the potential modes of inheritance or the hereditary influences underlying the development of cardiomyopathies, since these may aid in diagnosing such diseases in both sexes.
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