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Abstract Background Heart failure- (HF) and arrhythmia-related complications are the main causes of morbidity and mortality in patients with nonischemic dilated cardiomyopathy (NIDCM). Cardiovascular magnetic resonance (CMR) imaging is a noninvasive tool for risk stratification based on fibrosis assessment. Diffuse interstitial fibrosis in NIDCM may be a limitation for fibrosis assessment through late gadolinium enhancement (LGE), which might be overcome through quantitative T1 and extracellular volume (ECV) assessment. T1 and ECV prognostic value for arrhythmia-related events remain poorly investigated. We asked whether T1 and ECV have a prognostic value in NIDCM patients. Methods This prospective multicenter study analyzed 225 patients with NIDCM confirmed by CMR who were followed up for 2 years. CMR evaluation included LGE, native T1 mapping and ECV values. The primary endpoint was the occurrence of a major adverse cardiovascular event (MACE) which was divided in two groups: HF-related events and arrhythmia-related events. Optimal cutoffs for prediction of MACE occurrence were calculated for all CMR quantitative values. Results Fifty-eight patients (26%) developed a MACE during follow-up, 42 patients (19%) with HF-related events and 16 patients (7%) arrhythmia-related events. T1 Z-score (p = 0.008) and global ECV (p = 0.001) were associated with HF-related events occurrence, in addition to left ventricular ejection fraction (p 32.1% (optimal cutoff) remained the only CMR independent predictor of HF-related events occurrence (HR 2.15 [1.14–4.07], p = 0.018). In the arrhythmia-related events group, patients had increased native T1 Z-score and ECV values, with both T1 Z-score > 4.2 and ECV > 30.5% (optimal cutoffs) being independent predictors of arrhythmia-related events occurrence (respectively, HR 2.86 [1.06–7.68], p = 0.037 and HR 2.72 [1.01–7.36], p = 0.049). Conclusions ECV was the sole independent predictive factor for both HF- and arrhythmia-related events in NIDCM patients. Native T1 was also an independent predictor in arrhythmia-related events occurrence. The addition of ECV and more importantly native T1 in the decision-making algorithm may improve arrhythmia risk stratification in NIDCM patients. Trial registration NCT02352129. Registered 2nd February 2015—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02352129

BackgroundCurrent treatments of chemotherapy-induced cardiomyopathy (CCM) are of limited efficacy. We assessed whether repeated intravenous injections of human extracellular vesicles from cardiac progenitor cells (EV-CPC) could represent a new therapeutic option and whether EV manufacturing according to a Good Manufacturing Practices (GMP)-compatible process did not impair their bioactivity.MethodsImmuno-competent mice received intra-peritoneal injections (IP) of doxorubicin (DOX) (4 mg/kg each; cumulative dose: 12 mg/kg) and were then intravenously (IV) injected three times with EV-CPC (total dose: 30 billion). Cardiac function was assessed 9–11 weeks later by cardiac magnetic resonance imaging (CMR) using strain as the primary end point. Then, immuno-competent rats received 5 IP injections of DOX (3 mg/kg each; cumulative dose 15 mg/kg) followed by 3 equal IV injections of GMP-EV (total dose: 100 billion). Cardiac function was assessed by two dimensional-echocardiography.ResultsIn the chronic mouse model of CCM, DOX + placebo-injected hearts incurred a significant decline in basal (global, epi- and endocardial) circumferential strain compared with sham DOX-untreated mice (p = 0.043, p = 0.042, p = 0.048 respectively) while EV-CPC preserved these indices. Global longitudinal strain followed a similar pattern. In the rat model, IV injections of GMP-EV also preserved left ventricular end-systolic and end-diastolic volumes compared with untreated controls.ConclusionsIntravenously-injected extracellular vesicles derived from CPC have cardio-protective effects which may make them an attractive user-friendly option for the treatment of CCM.

ObjectivesMyocardial injury assessment from delayed enhancement magnetic resonance images is routinely limited to global descriptors such as size and transmurality. Statistical tools from computational anatomy can drastically improve this characterization, and refine the assessment of therapeutic procedures aiming at infarct size reduction. Based on these techniques, we propose a new characterization of myocardial injury up to the pixel resolution. We demonstrate it on the imaging data from the Minimalist Immediate Mechanical Intervention randomized clinical trial (MIMI: NCT01360242), which aimed at comparing immediate and delayed stenting in acute ST-Elevation Myocardial Infarction (STEMI) patients.MethodsWe analyzed 123 patients from the MIMI trial (62 ± 12 years, 98 male, 65 immediate 58 delayed stenting). Early and late enhancement images were transported onto a common geometry using techniques inspired by statistical atlases, allowing pixel-wise comparisons across population subgroups. A practical visualization of lesion patterns against specific clinical and therapeutic characteristics was also proposed using state-of-the-art dimensionality reduction.ResultsInfarct patterns were roughly comparable between the two treatments across the whole myocardium. Subtle but significant local differences were observed for the LCX and RCA territories with higher transmurality for delayed stenting at lateral and inferior/inferoseptal locations, respectively (15% and 23% of myocardial locations with a p-value

IntroductionCardioprotection strategies remain a new frontier in treating acute myocardial infarction (AMI), aiming at further protect the myocardium from the ischemia-reperfusion damage. Therefore, we aimed at investigating the mechano-transduction effects induced by shock waves (SW) therapy at time of the ischemia reperfusion as a non-invasive cardioprotective innovative approach to trigger healing molecular mechanisms.MethodsWe evaluated the SW therapy effects in an open-chest pig ischemia-reperfusion (IR) model, with quantitative cardiac Magnetic Resonance (MR) imaging performed along the experiments at multiple time points (baseline (B), during ischemia (I), at early reperfusion (ER) (∼15 min), and late reperfusion (LR) (3 h)). AMI was obtained by a left anterior artery temporary occlusion (50 min) in 18 pigs (32 ± 1.9 kg) randomized into SW therapy and control groups. In the SW therapy group, treatment was started at the end of the ischemia period and extended during early reperfusion (600 + 1,200 shots @0.09 J/mm2, f = 5 Hz). The MR protocol included at all time points LV global function assessment, regional strain quantification, native T1 and T2 parametric mapping. Then, after contrast injection (gadolinium), we obtained late gadolinium imaging and extra-cellular volume (ECV) mapping. Before animal sacrifice, Evans blue dye was administrated after re-occlusion for area-at-risk sizing.ResultsDuring ischemia, LVEF decreased in both groups (25 ± 4.8% in controls (p = 0.031), 31.6 ± 3.2% in SW (p = 0.02). After reperfusion, left ventricular ejection fraction (LVEF) remained significantly decreased in controls (39.9 ± 4% at LR vs. 60 ± 5% at baseline (p = 0.02). In the SW group, LVEF increased quickly ER (43.7 ± 11.4% vs. 52.4 ± 8.2%), and further improved at LR (49.4 ± 10.1) (ER vs. LR p = 0.05), close to baseline reference (LR vs. B p = 0.92). Furthermore, there was no significant difference in myocardial relaxation time (i.e. edema) after reperfusion in the intervention group compared to the control group: ΔT1 (MI vs. remote) was increased by 23.2±% for SW vs. +25.2% for the controls, while ΔT2 (MI vs. remote) increased by +24.9% for SW vs. +21.7% for the control group.DiscussionIn conclusion, we showed in an ischemia-reperfusion open-chest swine model that SW therapy, when applied near the relief of 50′ LAD occlusion, led to a nearly immediate cardioprotective effect translating to a reduction in the acute ischemia-reperfusion lesion size and to a significant LV function improvement. These new and promising results related to the multi-targeted effects of SW therapy in IR injury need to be confirmed by further in-vivo studies in close chest models with longitudinal follow-up.

Abstract Background While multiple cardiovascular magnetic resonance (CMR) methods provide excellent reproducibility of global circumferential and global longitudinal strain, achieving highly reproducible segmental strain is more challenging. Previous single-center studies have demonstrated excellent reproducibility of displacement encoding with stimulated echoes (DENSE) segmental circumferential strain. The present study evaluated the reproducibility of DENSE for measurement of whole-slice or global circumferential (Ecc), longitudinal (Ell) and radial (Err) strain, torsion, and segmental Ecc at multiple centers. Methods Six centers participated and a total of 81 subjects were studied, including 60 healthy subjects and 21 patients with various types of heart disease. CMR utilized 3 T scanners, and cine DENSE images were acquired in three short-axis planes and in the four-chamber long-axis view. During one imaging session, each subject underwent two separate DENSE scans to assess inter-scan reproducibility. Each subject was taken out of the scanner and repositioned between the scans. Intra-user, inter-user-same-site, inter-user-different-site, and inter-user-Human-Deep-Learning (DL) comparisons assessed the reproducibility of different users analyzing the same data. Inter-scan comparisons assessed the reproducibility of DENSE from scan to scan. The reproducibility of whole-slice or global Ecc, Ell and Err, torsion, and segmental Ecc were quantified using Bland–Altman analysis, the coefficient of variation (CV), and the intraclass correlation coefficient (ICC). CV was considered excellent for CV ≤ 10%, good for 10% 40. ICC values were considered excellent for ICC > 0.74, good for ICC 0.6

Fasting provokes fundamental changes in the activation of metabolic and signaling pathways leading to longer and healthier lifespans in animal models. Although the involvement of different metabolites in fueling human fasting metabolism is well known, the contribution of tissues and organs to their supply remains partly unclear. Also, changes in organ volume and composition remain relatively unexplored. Thus, processes involved in remodeling tissues during fasting and food reintroduction need to be better understood. Therefore, this study will apply state-of-the-art techniques to investigate the effects of long-term fasting (LF) and food reintroduction in humans by a multi-systemic approach focusing on changes in body composition, organ and tissue volume, lipid transport and storage, sources of protein utilization, blood metabolites, and gut microbiome profiles in a single cohort. This is a prospective, single-arm, monocentric trial. One hundred subjects will be recruited and undergo 9 ± 3 day-long fasting periods (250 kcal/day). We will assess changes in the composition of organs, bones and blood lipid profiles before and after fasting, as well as high-density lipoprotein (HDL) transport and storage, untargeted metabolomics of peripheral blood mononuclear cells (PBMCs), protein persulfidation and shotgun metagenomics of the gut microbiome. The first 32 subjects, fasting for 12 days, will be examined in more detail by magnetic resonance imaging (MRI) and spectroscopy to provide quantitative information on changes in organ volume and function, followed by an additional follow-up examination after 1 and 4 months. The study protocol was approved by the ethics board of the State Medical Chamber of Baden-Württemberg on 26.07.2021 and registered at ClinicalTrials.gov (NCT05031598). The results will be disseminated through peer-reviewed publications, international conferences and social media.Clinical trial registration[ClinicalTrials.gov], identifier [NCT05031598].

ObjectivesThe effects of ultra-distance on cardiac remodeling and fibrosis are unclear. Moreover, there are no data reporting the kinetics of cardiac alterations throughout the event and during recovery. Our aim was to investigate the kinetics of biological markers including new cardiac fibrosis biomarkers suppression of tumorigenicity 2 (ST2) and galectin-3 (Gal-3) during and after an extreme mountain ultramarathon.MethodsFifty experienced runners participating in one of the most challenging mountain ultramarathons (330 km, D+ 25,000 m) were enrolled in our study. Blood samples were collected at four time points: before (Pre-), at 148 km (Mid-), at the finish line (Post-), and 3 days after the recovery period (Recov-).ResultsThe cardiac fibrosis biomarkers (ST2 and Gal-3) increased from Pre- to Mid-. During the second half, ST2 remained higher than pre-values as opposed to Gal-3. Necrosis, ischemia, and myocyte injury biomarkers increased until Mid- then decreased but remained higher at Recov- than Pre-values. Oxidative stress appeared at Mid-. Lipid peroxides remained higher at Recov- compared to Pre-. The maximal value in most of these biomarkers was observed at Mid- and not at Post-.ConclusionsThe present study supports biphasic kinetics of cardiac fibrosis biomarkers, with a relative recovery during the second half of the event that seems specific to this extreme event. Overall, performing at such an extreme ultramarathon seems less deleterious for the heart than shorter events.

In the last decade, a large number of clinical trials have been deployed using Cardiac Magnetic Resonance (CMR) to evaluate cardioprotective strategies aiming at reducing the irreversible myocardial damage at the time of reperfusion. In these studies, segmentation and quantification of myocardial infarct lesion are often performed with a commercial software or an in-house closed-source code development thus creating a barrier for reproducible research. This paper introduces CMRSegTools: an open-source application software designed for the segmentation and quantification of myocardial infarct lesion enabling full access to state-of-the-art segmentation methods and parameters, easy integration of new algorithms and standardised results sharing. This post-processing tool has been implemented as a plug-in for the OsiriX/Horos DICOM viewer leveraging its database management functionalities and user interaction features to provide a bespoke tool for the analysis of cardiac MR images on large clinical cohorts. CMRSegTools includes, among others, user-assisted segmentation of the left-ventricle, semi- and automatic lesion segmentation methods, advanced statistical analysis and visualisation based on the American Heart Association 17-segment model. New segmentation methods can be integrated into the plug-in by developing components based on image processing and visualisation libraries such as ITK and VTK in C++ programming language. CMRSegTools allows the creation of training and testing data sets (labeled features such as lesion, microvascular obstruction and remote ROI) for supervised Machine Learning methods, and enables the comparative assessment of lesion segmentation methods via a single and integrated platform. The plug-in has been successfully used by several CMR imaging studies.

Abstract Background The T 1 Mapping and Extracellular volume (ECV) Standardization (T1MES) program explored T 1 mapping quality assurance using a purpose-developed phantom with Food and Drug Administration (FDA) and Conformité Européenne (CE) regulatory clearance. We report T 1 measurement repeatability across centers describing sequence, magnet, and vendor performance. Methods Phantoms batch-manufactured in August 2015 underwent 2 years of structural imaging, B 0 and B 1, and “reference” slow T 1 testing. Temperature dependency was evaluated by the United States National Institute of Standards and Technology and by the German Physikalisch-Technische Bundesanstalt. Center-specific T 1 mapping repeatability (maximum one scan per week to minimum one per quarter year) was assessed over mean 358 (maximum 1161) days on 34 1.5 T and 22 3 T magnets using multiple T 1 mapping sequences. Image and temperature data were analyzed semi-automatically. Repeatability of serial T 1 was evaluated in terms of coefficient of variation (CoV), and linear mixed models were constructed to study the interplay of some of the known sources of T 1 variation. Results Over 2 years, phantom gel integrity remained intact (no rips/tears), B 0 and B 1 homogenous, and “reference” T 1 stable compared to baseline (% change at 1.5 T, 1.95 ± 1.39%; 3 T, 2.22 ± 1.44%). Per degrees Celsius, 1.5 T, T 1 (MOLLI 5s(3s)3s) increased by 11.4 ms in long native blood tubes and decreased by 1.2 ms in short post-contrast myocardium tubes. Agreement of estimated T 1 times with “reference” T 1 was similar across Siemens and Philips CMR systems at both field strengths (adjusted R 2 ranges for both field strengths, 0.99–1.00). Over 1 year, many 1.5 T and 3 T sequences/magnets were repeatable with mean CoVs

Cardiac magnetic resonance myocardial perfusion imaging can detect coronary artery disease and is an alternative to single-photon emission computed tomography or positron emission tomography. However, the complex, non-linear MR signal and the lack of robust quantification of myocardial blood flow have hindered its widespread clinical application thus far. Recently, a new Bayesian approach was developed for brain imaging and evaluation of perfusion indexes (Kudo et al., 2014). In addition to providing accurate perfusion measurements, this probabilistic approach appears more robust than previous approaches, particularly due to its insensitivity to bolus arrival delays. We assessed the performance of this approach against a well-known and commonly deployed model-independent method based on the Fermi function for cardiac magnetic resonance myocardial perfusion imaging. The methods were first evaluated for accuracy and precision using a digital phantom to test them against the ground truth; next, they were applied in a group of coronary artery disease patients. The Bayesian method can be considered an appropriate model-independent method with which to estimate myocardial blood flow and delays. The digital phantom comprised a set of synthetic time-concentration curve combinations generated with a 2-compartment exchange model and a realistic combination of perfusion indexes, arterial input dynamics, noise and delays collected from the clinical dataset. The myocardial blood flow values estimated with the two methods showed an excellent correlation coefficient (r2 > 0.9) under all noise and delay conditions. The Bayesian approach showed excellent robustness to bolus arrival delays, with a similar performance to Fermi modeling when delays were considered. Delays were better estimated with the Bayesian approach than with Fermi modeling. An in vivo analysis of coronary artery disease patients revealed that the Bayesian approach had an excellent ability to distinguish between abnormal and normal myocardium. The Bayesian approach was able to discriminate not only flows but also delays with increased sensitivity by offering a clearly enlarged range of distribution for the physiologic parameters.

IntroductionMyocardial hemorrhage (IMH) and persistent microvascular obstruction (MVO) are associated with impaired myocardial recovery and adverse clinical outcomes in STEMI patients. However, their relationship with circulating inflammatory biomarkers is unclear in human patients.Methods and resultsTwenty consecutive patients referred for primary percutaneous coronary intervention of first STEMI were included in a prospective study. Blood sampling was performed at admission, 4, 12, 24, 48 hours, 7 and 30 days after reperfusion for inflammatory biomarker (C reactive protein, fibrinogen, interleukin-6 (IL-6) and neutrophils count) assessment. At seven days, cardiovascular magnetic resonance (CMR) was performed for infarct size, MVO and IMH assessment. Median infarct size was 24.6% Interquartile range (IQR) [12.0-43.5] of LV mass and edema was 13.2% IQR [7.7-36.1] of LV mass. IL-6 reached a peak at H24 (5.6 pg/mL interquartile range (IQR) [2.5-17.5]), CRP at H48 (11.7 mg/L IQR [7.1-69.2]), fibrinogen one week after admission (4.4 g/L IQR [3.8-6.7]) and neutrophils at H12 (9.0 G/L IQR [6.5-12.7]). MVO was present in 11 patients (55% of the study population) and hemorrhage in 7 patients (35%). Patients with IMH had significantly higher IL-6, CRP, fibrinogen, and neutrophils levels compared to patients without IMH. Patients with persistent MVO had significantly higher CRP, fibrinogen and neutrophils level compared to patients without MVO, but identical IL-6 kinetics.ConclusionIn human patients with acute myocardial infarction, intramyocardial hemorrhage appears to have a stronger relationship with inflammatory biomarker release compared to persistent MVO. Attenuating myocardial hemorrhage may be a novel target in future adjunctive STEMI treatments.

Objectives: The aim of this study was to investigate the feasibility of measuring the effects of a 14-day Periodic Fasting (PF) intervention (

The purpose of this study was to evaluate the performance of a semiautomatic segmentation method for the anatomical and functional assessment of both ventricles from cardiac cine magnetic resonance (MR) examinations, reducing user interaction to a “mouse-click”. Fifty-two patients with cardiovascular diseases were examined using a 1.5-T MR imaging unit. Several parameters of both ventricles, such as end-diastolic volume (EDV), end-systolic volume (ESV) and ejection fraction (EF), were quantified by an experienced operator using the conventional method based on manually-defined contours, as the standard of reference; and a novel semiautomatic segmentation method based on edge detection, iterative thresholding and region growing techniques, for evaluation purposes. No statistically significant differences were found between the two measurement values obtained for each parameter (p > 0.05). Correlation to estimate right ventricular function was good (r > 0.8) and turned out to be excellent (r > 0.9) for the left ventricle (LV). Bland-Altman plots revealed acceptable limits of agreement between the two methods (95%). Our study findings indicate that the proposed technique allows a fast and accurate assessment of both ventricles. However, further improvements are needed to equal results achieved for the right ventricle (RV) using the conventional methodology.

In sports medicine, there is increasing interest in quantifying the elastic properties of skeletal muscle, especially during extreme muscular stimulation, to improve our understanding of the impact of alterations in skeletal muscle stiffness on resulting pain or injuries, as well as the mechanisms underlying the relationships between these parameters. Our main objective was to determine whether real-time shear-wave elastography (SWE) can monitor changes in quadriceps muscle elasticity during an extreme mountain ultra-marathon, a powerful mechanical stress model. Our study involved 50 volunteers participating in an extreme mountain marathon (distance: 330 km, elevation: +24,000 m). Quantitative SWE velocity and shear modulus measurements were performed in most superficial quadriceps muscle heads at the following 4 time points: before the race, halfway through the race, upon finishing the race and after recovery (+48 h). Blood biomarker levels were also measured. A significant decrease in the quadriceps shear modulus was observed upon finishing the race (3.31±0.61 kPa) (p

[This corrects the article DOI: 10.1371/journal.pone.0161855.].

Objective: Muscle atrophy is frequent in critically ill patients and is associated with increased mortality and long-lasting alteration in quality of life. Muscle ultrasound has not been clearly validated in intensive care unit patients. The aim of this study was to compare the level of agreement between ultrasound and computed tomography scan for the measurement of quadriceps muscle thickness. Design: A prospective observational study. Patients: Forty-two consecutive patients admitted to a neurological intensive care unit. Methods: Quadriceps thickness was measured 15 cm above the upper edge of the patella. Iterative brain computed tomography scans were associated with a quadriceps-centred acquisition sequence. Concomitantly, an ultrasound of the quadriceps was performed. The position of the studied leg was standardized for ultrasound and computed tomography. Results: A total of 73 measurements of ultrasound and computed tomography quadriceps thickness were compared. The correlation between both measures was 0.93 (95% confidence interval (95% CI) 0.84–1.02). Intra-rater reliability of ultrasound measurements and inter-rater reliability were excellent, with an ICC of 0.98 (95% CI 0.97–0.99) and 0.96 (95% CI 0.92–0.98), respectively. Conclusion: A specific ultrasound set-up for measurement of quadriceps thickness is reliable and reproducible in an intensive care unit population.