Myocardial extracellular volume quantification by cardiovascularagn magnetic resonance and computed tomography

Purpose of review This review article discusses the evolution of extracellular volume (ECV) quantification using both cardiovascular magnetic resonance (CMR) and computed tomography (CT). Recent findings Visualizing diffuse myocardial fibrosis is challenging and until recently, was restricted to the domain of the pathologist. CMR and CT both use extravascular, extracellular contrast agents, permitting ECV measurement. The evidence base around ECV quantification by CMR is growing rapidly and just starting in CT. In conditions with high ECV (amyloid, oedema and fibrosis), this technique is already being used clinically and as a surrogate endpoint. Non-invasive diffuse fibrosis quantification is also generating new biological insights into key cardiac diseases. Summary CMR and CT can estimate ECV and in turn diffuse myocardial fibrosis, obviating the need for invasive endomyocardial biopsy. CT is an attractive alternative to CMR particularly in those individuals with contraindications to the latter. Further studies are needed, particularly in CT

Cardiac phase-resolved late gadolinium enhancement imaging

Late gadolinium enhancement (LGE) with cardiac magnetic resonance (CMR) imaging is the clinical reference for assessment of myocardial scar and focal fibrosis. However, current LGE techniques are confined to imaging of a single cardiac phase, which hampers assessment of scar motility and does not allow cross-comparison between multiple phases. In this work, we investigate a three step approach to obtain cardiac phase-resolved LGE images: (1) Acquisition of cardiac phase-resolved imaging data with varying T(1) weighting. (2) Generation of semi-quantitative T(*)(1) maps for each cardiac phase. (3) Synthetization of LGE contrast to obtain functional LGE images. The proposed method is evaluated in phantom imaging, six healthy subjects at 3T and 20 patients at 1.5T. Phantom imaging at 3T demonstrates consistent contrast throughout the cardiac cycle with a coefficient of variation of 2.55 ± 0.42%. In-vivo results show reliable LGE contrast with thorough suppression of the myocardial tissue is healthy subjects. The contrast between blood and myocardium showed moderate variation throughout the cardiac cycle in healthy subjects (coefficient of variation 18.2 ± 3.51%). Images were acquired at 40–60 ms and 80 ms temporal resolution, at 3T and 1.5, respectively. Functional LGE images acquired in patients with myocardial scar visualized scar tissue throughout the cardiac cycle, albeit at noticeably lower imaging resolution and noise resilience than the reference technique. The proposed technique bears the promise of integrating the advantages of phase-resolved CMR with LGE imaging, but further improvements in the acquisition quality are warranted for clinical use

Validation of four-dimensional flow cardiovascular magnetic resonance for aortic stenosis assessment

The management of patients with aortic stenosis (AS) crucially depends on accurate diagnosis. The main aim of this study were to validate the four-dimensional flow (4D flow) cardiovascular magnetic resonance (CMR) methods for AS assessment. Eighteen patients with clinically severe AS were recruited. All patients had pre-valve intervention 6MWT, echocardiography and CMR with 4D flow. Of these, ten patients had a surgical valve replacement, and eight patients had successful transcatheter aortic valve implantation (TAVI). TAVI patients had invasive pressure gradient assessments. A repeat assessment was performed at 3–4 months to assess the remodelling response. The peak pressure gradient by 4D flow was comparable to an invasive pressure gradient (54 ± 26 mmHG vs 50 ± 34 mmHg, P = 0.67). However, Doppler yielded significantly higher pressure gradient compared to invasive assessment (61 ± 32 mmHG vs 50 ± 34 mmHg, P = 0.0002). 6MWT was associated with 4D flow CMR derived pressure gradient (r = −0.45, P = 0.01) and EOA (r = 0.54, P < 0.01) but only with Doppler EOA (r = 0.45, P = 0.01). Left ventricular mass regression was better associated with 4D flow derived pressure gradient change (r = 0.64, P = 0.04). 4D flow CMR offers an alternative method for non-invasive assessment of AS. In addition, 4D flow derived valve metrics have a superior association to prognostically relevant 6MWT and LV mass regression than echocardiography

Sex dimorphism in the myocardial response to aortic stenosis

Objectives: The goal of this study was to explore sex differences in myocardial remodeling in aortic stenosis (AS) by using echocardiography, cardiac magnetic resonance (CMR), and biomarkers. Background: AS is a disease of both valve and left ventricle (LV). Sex differences in LV remodeling are reported in AS and may play a role in disease phenotyping. Methods: This study was a prospective assessment of patients awaiting surgical valve replacement for severe AS using echocardiography, the 6-min walking test, biomarkers (high-sensitivity troponin T and N-terminal pro-brain natriuretic peptide), and CMR with late gadolinium enhancement and extracellular volume fraction, which dichotomizes the myocardium into matrix and cell volumes. LV remodeling was categorized into normal geometry, concentric remodeling, concentric hypertrophy, and eccentric hypertrophy

Myocardial fibrosis in asymptomatic and symptomatic chronic severe primary mitral regurgitation and relationship to tissue characterisation and left ventricular function on cardiovascular magnetic resonance

Background: Myocardial fbrosis occurs in end-stage heart failure secondary to mitral regurgitation (MR), but it is not known whether this is present before onset of symptoms or myocardial dysfunction. This study aimed to characterise myocardial fbrosis in chronic severe primary MR on histology, compare this to tissue characterisation on cardiovascular magnetic resonance (CMR) imaging, and investigate associations with symptoms, left ventricular (LV) function, and exercise capacity. Methods: Patients with class I or IIa indications for surgery underwent CMR and cardiopulmonary exercise testing. LV biopsies were taken at surgery and the extent of fbrosis was quantifed on histology using collagen volume fraction (CVFmean) compared to autopsy controls without cardiac pathology. Results: 120 consecutive patients (64±13 years; 71% male) were recruited; 105 patients underwent MV repair while 15 chose conservative management. LV biopsies were obtained in 86 patients (234 biopsy samples in total). MR patients had more fbrosis compared to 8 autopsy controls (median: 14.6% [interquartile range 7.4–20.3] vs. 3.3% [2.6–6.1], P<0.001); this diference persisted in the asymptomatic patients (CVFmean 13.6% [6.3–18.8], P<0.001), but severity of fbrosis was not signifcantly higher in NYHA II-III symptomatic MR (CVFmean 15.7% [9.9–23.1] (P=0.083). Fibrosis was patchy across biopsy sites (intraclass correlation 0.23, 95% CI 0.08–0.39, P=0.001). No signifcant relationships were identifed between CVFmean and CMR tissue characterisation [native T1, extracellular volume (ECV) or late gadolinium enhancement] or measures of LV function [LV ejection fraction (LVEF), global longitudinal strain (GLS)]. Although the range of ECV was small (27.3±3.2%), ECV correlated with multiple measures of LV function (LVEF: Rho=−0.22, P=0.029, GLS: Rho=0.29, P=0.003), as well as NTproBNP (Rho=0.54, P<0.001) and exercise capacity (%PredVO2max: R=−0.22, P=0.030). Conclusions: Patients with chronic primary MR have increased fbrosis before the onset of symptoms. Due to the patchy nature of fbrosis, CMR derived ECV may be a better marker of global myocardial status. Clinical trial registration Mitral FINDER study; Clinical Trials NCT02355418, Registered 4 February 2015, https://clinicaltr ials.gov/ct2/show/NCT0235541

Mitral regurgitation quantification by cardiac magnetic resonance imaging (MRI) remains reproducible between software solutions [version 3; peer review: 2 approved]

Background: The reproducibility of mitral regurgitation (MR) quantification by cardiovascular magnetic resonance (CMR) imaging using different software solutions remains unclear. This research aimed to investigate the reproducibility of MR quantification between two software solutions: MASS (version 2019 EXP, LUMC, Netherlands) and CAAS (version 5.2, Pie Medical Imaging). Methods: CMR data of 35 patients with MR (12 primary MR, 13 mitral valve repair/replacement, and ten secondary MR) was used. Four methods of MR volume quantification were studied, including two 4D-flow CMR methods (MRMVAV and MRJet) and two non-4D-flow techniques (MRStandard and MRLVRV). We conducted within-software and inter-software correlation and agreement analyses. Results: All methods demonstrated significant correlation between the two software solutions: MRStandard (r=0.92, p<0.001), MRLVRV (r=0.95, p<0.001), MRJet (r=0.86, p<0.001), and MRMVAV (r=0.91, p<0.001). Between CAAS and MASS, MRJet and MRMVAV, compared to each of the four methods, were the only methods not to be associated with significant bias. Conclusions: We conclude that 4D-flow CMR methods demonstrate equivalent reproducibility to non-4D-flow methods but greater levels of agreement between software solutions

Mitral regurgitation quantification by cardiac magnetic resonance imaging (MRI) remains reproducible between software solutions [version 1; peer review: 1 approved with reservations]

Background: The reproducibility of mitral regurgitation (MR) quantification by cardiovascular magnetic resonance (CMR) imaging using different software solutions remains unclear. This research aimed to investigate the reproducibility of MR quantification between two software solutions: MASS (version 2019 EXP, LUMC, Netherlands) and CAAS (version 5.2, Pie Medical Imaging). Methods: CMR data of 35 patients with MR (12 primary MR, 13 mitral valve repair/replacement, and ten secondary MR) was used. Four methods of MR volume quantification were studied, including two 4D-flow CMR methods (MRMVAV and MRJet) and two non-4D-flow techniques (MRStandard and MRLVRV). We conducted within-software and inter-software correlation and agreement analyses. Results: All methods demonstrated significant correlation between the two software solutions: MRStandard (r=0.92, p<0.001), MRLVRV (r=0.95, p<0.001), MRJet (r=0.86, p<0.001), and MRMVAV (r=0.91, p<0.001). Between CAAS and MASS, MRJet and MRMVAV, compared to each of the four methods, were the only methods not to be associated with significant bias. Conclusions: We conclude that 4D-flow CMR methods demonstrate equivalent reproducibility to non-4D-flow methods but greater levels of agreement between software solutions

H3K27ac acetylome signatures reveal the epigenomic reorganization in remodeled non-failing human hearts

BACKGROUND: H3K27ac histone acetylome changes contribute to the phenotypic response in heart diseases, particularly in end-stage heart failure. However, such epigenetic alterations have not been systematically investigated in remodeled non-failing human hearts. Therefore, valuable insight into cardiac dysfunction in early remodeling is lacking. This study aimed to reveal the acetylation changes of chromatin regions in response to myocardial remodeling and their correlations to transcriptional changes of neighboring genes. RESULTS: We detected chromatin regions with differential acetylation activity (DARs; Padj. < 0.05) between remodeled non-failing patient hearts and healthy donor hearts. The acetylation level of the chromatin region correlated with its RNA polymerase II occupancy level and the mRNA expression level of its adjacent gene per sample. Annotated genes from DARs were enriched in disease-related pathways, including fibrosis and cell metabolism regulation. DARs that change in the same direction have a tendency to cluster together, suggesting the well-reorganized chromatin architecture that facilitates the interactions of regulatory domains in response to myocardial remodeling. We further show the differences between the acetylation level and the mRNA expression level of cell-type-specific markers for cardiomyocytes and 11 non-myocyte cell types. Notably, we identified transcriptome factor (TF) binding motifs that were enriched in DARs and defined TFs that were predicted to bind to these motifs. We further showed 64 genes coding for these TFs that were differentially expressed in remodeled myocardium when compared with controls. CONCLUSIONS: Our study reveals extensive novel insight on myocardial remodeling at the DNA regulatory level. Differences between the acetylation level and the transcriptional level of cell-type-specific markers suggest additional mechanism(s) between acetylome and transcriptome. By integrating these two layers of epigenetic profiles, we further provide promising TF-encoding genes that could serve as master regulators of myocardial remodeling. Combined, our findings highlight the important role of chromatin regulatory signatures in understanding disease etiology

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification. Funding: UK Research and Innovation and National Institute for Health Research

Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain–gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials