Search

Objectives Cardiac MR is widely used to diagnose cardiac amyloid, but cannot differentiate AL and ATTR subtypes: an important distinction given their differing treatments and prognoses. We used PET/MR imaging to quantify myocardial uptake of 18F-fluoride in ATTR and AL amyloid patients, as well as participants with aortic stenosis and age/sex-matched controls. Methods In this prospective multicenter study, patients were recruited in Edinburgh and New York and underwent 18F-fluoride PET/MR imaging. Standardized volumes of interest were drawn in the septum and areas of late gadolinium enhancement to derive myocardial standardized uptake values (SUV) and tissue-to-background ratio (TBRMEAN) after correction for blood pool activity in the right atrium. Results 53 patients were scanned: 18 with cardiac amyloid (10 ATTR and 8 AL), 13 controls, and 22 with aortic stenosis. No differences in myocardial TBR values were observed between participants scanned in Edinburgh and New York. Mean myocardial TBRMEAN values in ATTR amyloid (1.13 ± 0.16) were higher than controls (0.84 ± 0.11, P = .0006), aortic stenosis (0.73 ± 0.12, P < .0001), and those with AL amyloid (0.96 ± 0.08, P = .01). TBRMEAN values within areas of late gadolinium enhancement provided discrimination between patients with ATTR (1.36 ± 0.23) and all other groups (e.g., AL [1.06 ± 0.07, P = .003]). A TBRMEAN threshold >1.14 in areas of LGE demonstrated 100% sensitivity (CI 72.25 to 100%) and 100% specificity (CI 67.56 to 100%) for ATTR compared to AL amyloid (AUC 1, P = .0004). Conclusion Quantitative 18F-fluoride PET/MR imaging can distinguish ATTR amyloid from other similar phenotypes and holds promise in improving the diagnosis of this condition.

Visual Abstract, Myocardial infarction (MI) is one of the leading causes of death worldwide, and inflammation is central to tissue response and patient outcomes. The 18-kDa translocator protein (TSPO) has been used in PET as an inflammatory biomarker. The aims of this study were to screen novel, fluorinated, TSPO radiotracers for susceptibility to the rs6971 genetic polymorphism using in vitro competition binding assays in human brain and heart; assess whether the in vivo characteristics of our lead radiotracer, 18F-LW223, are suitable for clinical translation; and validate whether 18F-LW223 can detect macrophage-driven inflammation in a rat MI model. Methods: Fifty-one human brain and 29 human heart tissue samples were screened for the rs6971 polymorphism. Competition binding assays were conducted with 3H-PK11195 and the following ligands: PK11195, PBR28, and our novel compounds (AB5186 and LW223). Naïve rats and mice were used for in vivo PET kinetic studies, radiometabolite studies, and dosimetry experiments. Rats underwent permanent coronary artery ligation and were scanned using PET/CT with an invasive input function at 7 d after MI. For quantification of PET signal in the hypoperfused myocardium, K1 (rate constant for transfer from arterial plasma to tissues) was used as a surrogate marker of perfusion to correct the binding potential for impaired radiotracer transfer from plasma to tissue (BPTC). Results: LW223 binding to TSPO was not susceptible to the rs6971 genetic polymorphism in human brain and heart samples. In rodents, 18F-LW223 displayed a specific uptake consistent with TSPO expression, a slow metabolism in blood (69% of parent at 120 min), a high plasma free fraction of 38.5%, and a suitable dosimetry profile (effective dose of 20.5–24.5 μSv/MBq). 18F-LW223 BPTC was significantly higher in the MI cohort within the infarct territory of the anterior wall relative to the anterior wall of naïve animals (32.7 ± 5.0 vs. 10.0 ± 2.4 cm3/mL/min, P ≤ 0.001). Ex vivo immunofluorescent staining for TSPO and CD68 (macrophage marker) resulted in the same pattern seen with in vivo BPTC analysis. Conclusion: 18F-LW223 is not susceptible to the rs6971 genetic polymorphism in in vitro assays, has favorable in vivo characteristics, and is able to accurately map macrophage-driven inflammation after MI.

ObjectivesTo determine the contribution of comorbidities on the reported widespread myocardial abnormalities in patients with recent COVID-19.MethodsIn a prospective two-centre observational study, patients hospitalised with confirmed COVID-19 underwent gadolinium and manganese-enhanced MRI and CT coronary angiography (CTCA). They were compared with healthy and comorbidity-matched volunteers after blinded analysis.ResultsIn 52 patients (median age: 54 (IQR 51–57) years, 39 males) who recovered from COVID-19, one-third (n=15, 29%) were admitted to intensive care and a fifth (n=11, 21%) were ventilated. Twenty-three patients underwent CTCA, with one-third having underlying coronary artery disease (n=8, 35%). Compared with younger healthy volunteers (n=10), patients demonstrated reduced left (ejection fraction (EF): 57.4±11.1 (95% CI 54.0 to 60.1) versus 66.3±5 (95 CI 62.4 to 69.8)%; p=0.02) and right (EF: 51.7±9.1 (95% CI 53.9 to 60.1) vs 60.5±4.9 (95% CI 57.1 to 63.2)%; p≤0.0001) ventricular systolic function with elevated native T1 values (1225±46 (95% CI 1205 to 1240) vs 1197±30 (95% CI 1178 to 1216) ms;p=0.04) and extracellular volume fraction (ECV) (31±4 (95% CI 29.6 to 32.1) vs 24±3 (95% CI 22.4 to 26.4)%; pConclusionsPatients demonstrate right but not left ventricular dysfunction. Previous reports of left ventricular myocardial abnormalities following COVID-19 may reflect pre-existing comorbidities.Trial registration numberNCT04625075.

Background First-phase ejection fraction (EF1; the ejection fraction measured during active systole up to the time of maximal aortic flow) measured by transthoracic echocardiography (TTE) is a powerful predictor of outcomes in patients with aortic stenosis. We aimed to assess whether cardiovascular magnetic resonance (CMR) might provide more precise measurements of EF1 than TTE and to examine the correlation of CMR EF1 with measures of fibrosis. Methods In 141 patients with at least mild aortic stenosis, we measured CMR EF1 from a short-axis 3D stack and compared its variability with TTE EF1, and its associations with myocardial fibrosis and clinical outcome (aortic valve replacement (AVR) or death). Results Intra- and inter-observer variation of CMR EF1 (standard deviations of differences within and between observers of 2.3% and 2.5% units respectively) was approximately 50% that of TTE EF1. CMR EF1 was strongly predictive of AVR or death. On multivariable Cox proportional hazards analysis, the hazard ratio for CMR EF1 was 0.93 (95% confidence interval 0.89–0.97, p = 0.001) per % change in EF1 and, apart from aortic valve gradient, CMR EF1 was the only imaging or biochemical measure independently predictive of outcome. Indexed extracellular volume was associated with AVR or death, but not after adjusting for EF1. Conclusions EF1 is a simple robust marker of early left ventricular impairment that can be precisely measured by CMR and predicts outcome in aortic stenosis. Its measurement by CMR is more reproducible than that by TTE and may facilitate left ventricular structure–function analysis.

Background Widespread abnormalities of the myocardium have been reported in patients with COVID-19. However, these patients often have substantial co-morbidities and it is essential to understand whether cardiac abnormalities represent pre-existing disease or are the consequence of COVID-19. Objective To determine the contribution and cardiac impact of co-morbidities in patients who have recovered from COVID-19. Methods In a prospective observational study, adult patients hospitalized with confirmed COVID-19 were recruited from the Edinburgh Heart Centre between May and November 2020 and compared to healthy and co-morbidity-matched volunteers. Patients underwent gadolinium and manganese-enhanced magnetic resonance imaging and coronary computed tomography angiography. Results Twenty-three patients (54±11 years, 20 male) who recovered from COVID-19 were recruited. Half (n=11, 48%) required admission to the intensive care unit and a third (n=7, 31%) received non-invasive or invasive ventilation. Patients had a high prevalence of known cardiovascular disease (n=18, 78%), associated risk factors (n=11, 45%) and coronary artery disease (n=8, 35%). Compared with younger healthy volunteers (n=10), myocardial native T1 values (1202±25 versus 1162±27 ms, P=0.008, figure 1) and extracellular volume fraction (31.9±1.7 versus 29.8±0.5 %, P=0.001, figure 1) were higher with no differences in manganese uptake. Compared to co-morbidity-matched volunteers (n=20), there were no differences in native T1 values (1202±25 versus 1196±39 ms, P=0.61, figure 1), extracellular volume fraction (31.9±1.7 versus 31.0±0.5 %, P=0.11), presence of late gadolinium enhancement or manganese uptake. These findings remained irrespective of COVID-19 disease severity, presence of concomitant myocardial injury or coronary artery disease. Conclusions Patients who have recovered following hospitalization with COVID-19 have no evidence of a major excess in myocardial injury or dysfunction compared to co-morbidity-matched volunteers. The presence of co-morbidities likely explains many of the previously reported myocardial abnormalities. Conflict of Interest None

Background: Acute stress-induced (takotsubo) cardiomyopathy can result in a heart failure phenotype with a prognosis comparable with that of myocardial infarction. In this study, we hypothesized that inflammation is central to the pathophysiology and natural history of takotsubo cardiomyopathy. Methods: In a multicenter study, we prospectively recruited 55 patients with takotsubo cardiomyopathy and 51 age-, sex-, and comorbidity-matched control subjects. During the index event and at the 5-month follow-up, patients with takotsubo cardiomyopathy underwent multiparametric cardiac magnetic resonance imaging, including ultrasmall superparamagnetic particles of iron oxide (USPIO) enhancement for detection of inflammatory macrophages in the myocardium. Blood monocyte subpopulations and serum cytokines were assessed as measures of systemic inflammation. Matched control subjects underwent investigation at a single time point. Results: Subjects were predominantly middle-aged (64±14 years) women (90%). Compared with control subjects, patients with takotsubo cardiomyopathy had greater USPIO enhancement (expressed as the difference between pre-USPIO and post-USPIO T2*) in both ballooning (14.3±0.6 milliseconds versus 10.5±0.9 milliseconds; P P =0.02) left ventricular myocardial segments. Serum interleukin-6 (23.1±4.5 pg/mL versus 6.5±5.8 pg/mL; P P =0.01) concentrations and classic CD14 ++ CD16 - monocytes (90±0.5% versus 87±0.9%; P =0.01) were also increased whereas intermediate CD14 ++ CD16 + (5.4±0.3% versus 6.9±0.6%; P =0.01) and nonclassic CD14 + CD16 ++ (2.7±0.3% versus 4.2±0.5%; P =0.006) monocytes were reduced in patients with takotsubo cardiomyopathy. At 5 months, USPIO enhancement was no longer detectable in the left ventricular myocardium, although persistent elevations in serum interleukin-6 concentrations ( P =0.009) and reductions in intermediate CD14 ++ CD16 + monocytes (5.6±0.4% versus 6.9±0.6%; P =0.01) remained. Conclusions: We demonstrate for the first time that takotsubo cardiomyopathy is characterized by a myocardial macrophage inflammatory infiltrate, changes in the distribution of monocyte subsets, and an increase in systemic proinflammatory cytokines. Many of these changes persisted for at least 5 months, suggesting a low-grade chronic inflammatory state. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02897739.

ObjectiveIn a proof-of-concept study, to quantify myocardial viability in patients with acute myocardial infarction using manganese-enhanced MRI (MEMRI), a measure of intracellular calcium handling.MethodsHealthy volunteers (n=20) and patients with ST-elevation myocardial infarction (n=20) underwent late gadolinium enhancement (LGE) using gadobutrol and MEMRI using manganese dipyridoxyl diphosphate. Patients were scanned ≤7 days after reperfusion and rescanned after 3 months. Differential manganese uptake was described using a two-compartment model.ResultsAfter manganese administration, healthy control and remote non-infarcted myocardium showed a sustained 25% reduction in T1 values (mean reductions, 288±34 and 281±12 ms). Infarcted myocardium demonstrated less T1 shortening than healthy control or remote myocardium (1157±74 vs 859±36 and 835±28 ms; both p2=0.72 vs 0.55; p0.1) myocardium.ConclusionsThrough visualisation of intracellular calcium handling, MEMRI accurately differentiates infarcted, stunned and viable myocardium, and correlates with myocardial dysfunction better than LGE. MEMRI holds major promise in directly assessing myocardial viability, function and calcium handling across a range of cardiac diseases.Trial registration numbersNCT03607669; EudraCT number 2016-003782-25.

Summary Background 3 billion people worldwide rely on polluting fuels and technologies for domestic cooking and heating. We estimate the global, regional, and national health burden associated with exposure to household air pollution. Methods For the systematic review and meta-analysis, we systematically searched four databases for studies published from database inception to April 2, 2020, that evaluated the risk of adverse cardiorespiratory, paediatric, and maternal outcomes from exposure to household air pollution, compared with no exposure. We used a random-effects model to calculate disease-specific relative risk (RR) meta-estimates. Household air pollution exposure was defined as use of polluting fuels (coal, wood, charcoal, agricultural wastes, animal dung, or kerosene) for household cooking or heating. Temporal trends in mortality and disease burden associated with household air pollution, as measured by disability-adjusted life-years (DALYs), were estimated from 2000 to 2017 using exposure prevalence data from 183 of 193 UN member states. 95% CIs were estimated by propagating uncertainty from the RR meta-estimates, prevalence of household air pollution exposure, and disease-specific mortality and burden estimates using a simulation-based approach. This study is registered with PROSPERO, CRD42019125060. Findings 476 studies (15·5 million participants) from 123 nations (99 [80%] of which were classified as low-income and middle-income) met the inclusion criteria. Household air pollution was positively associated with asthma (RR 1·23, 95% CI 1·11–1·36), acute respiratory infection in both adults (1·53, 1·22–1·93) and children (1·39, 1·29–1·49), chronic obstructive pulmonary disease (1·70, 1·47–1·97), lung cancer (1·69, 1·44–1·98), and tuberculosis (1·26, 1·08–1·48); cerebrovascular disease (1·09, 1·04–1·14) and ischaemic heart disease (1·10, 1·09–1·11); and low birthweight (1·36, 1·19–1·55) and stillbirth (1·22, 1·06–1·41); as well as with under-5 (1·25, 1·18–1·33), respiratory (1·19, 1·18–1·20), and cardiovascular (1·07, 1·04–1·11) mortality. Household air pollution was associated with 1·8 million (95% CI 1·1–2·7) deaths and 60·9 million (34·6–93·3) DALYs in 2017, with the burden overwhelmingly experienced in low-income and middle-income countries (LMICs; 60·8 million [34·6–92·9] DALYs) compared with high-income countries (0·09 million [0·01–0·40] DALYs). From 2000, mortality associated with household air pollution had reduced by 36% (95% CI 29–43) and disease burden by 30% (25–36), with the greatest reductions observed in higher-income nations. Interpretation The burden of cardiorespiratory, paediatric, and maternal diseases associated with household air pollution has declined worldwide but remains high in the world's poorest regions. Urgent integrated health and energy strategies are needed to reduce the adverse health impact of household air pollution, especially in LMICs. Funding British Heart Foundation, Wellcome Trust.

Introduction Cardiac MR is widely used to diagnose cardiac amyloid but cannot differentiate AL and ATTR subtypes: an important distinction given their differing treatments and prognoses. We used PET/MR imaging to quantify myocardial uptake of 18F-fluoride in ATTR and AL amyloid patients as well as participants with aortic stenosis and age/sex matched controls (both negative controls). Methods In this prospective multi-centre study, patients were recruited in Edinburgh and New York and underwent 18F-fluoride PET/MR imaging. Standardised volumes of interest were drawn in the septum and areas of late gadolinium enhancement to derive myocardial standardised uptake values (SUV) and tissue to background ratio (TBRMEAN) after correction for blood pool activity in the right atrium. Results 53 patients were scanned. 18 with cardiac amyloid (10 ATTR and 8 AL), 13 controls and 22 with aortic stenosis. No differences in myocardial TBR values were observed between participants scanned in Edinburgh and New York. Mean myocardial TBRMEAN values in ATTR amyloid (1.13±0.16) were significantly higher than controls (0.84±0.11, p=0.0006), aortic stenosis (0.73±0.12, p 1.14 in areas of LGE demonstrated 100% sensitivity (C.I. 72.25 – 100%) and 100% specificity (C.I. 67.56 – 100%) for ATTR compared to AL amyloid (AUC 1, p=0.0004). Conclusion Quantitative 18F-fluoride PET/MR imaging can distinguish ATTR amyloid from other similar phenotypes and holds major promise in improving the diagnosis of this condition and helping to tailor appropriate treatments to those most likely to benefit.

Aims The aim of this study is to quantify altered myocardial calcium handling in non-ischaemic cardiomyopathy using magnetic resonance imaging. Methods and results Patients with dilated cardiomyopathy (n = 10) or hypertrophic cardiomyopathy (n = 17) underwent both gadolinium and manganese contrast-enhanced magnetic resonance imaging and were compared with healthy volunteers (n = 20). Differential manganese uptake (Ki) was assessed using a two-compartment Patlak model. Compared with healthy volunteers, reduction in T1 with manganese-enhanced magnetic resonance imaging was lower in patients with dilated cardiomyopathy [mean reduction 257 ± 45 (21%) vs. 288 ± 34 (26%) ms, P Conclusion The rate of manganese uptake in both dilated and hypertrophic cardiomyopathy provides a measure of altered myocardial calcium handling. This holds major promise for the detection and monitoring of dysfunctional myocardium, with the potential for early intervention and prognostication.

ObjectiveFirst-phase ejection fraction (EF1) is a novel measure of early left ventricular systolic dysfunction. We investigated determinants of EF1 and its prognostic value in aortic stenosis.MethodsEF1 was measured retrospectively in participants of an echocardiography/cardiovascular magnetic resonance cohort study which recruited patients with aortic stenosis (peak aortic velocity of ≥2 m/s) between 2012 and 2014. Linear regression models were constructed to examine variables associated with EF1. Cox proportional hazards were used to determine the prognostic power of EF1 for aortic valve replacement (AVR, performed as part of clinical care in accordance with international guidelines) or death.ResultsTotal follow-up of the 149 participants (69.8% male, 70 (65–76) years, mean gradient 33 (21–42) mm Hg) was 238 029 person-days. Sixty-seven participants (45%) had a low baseline EF1 (2 vs 20.6 (16.8–24.3) mL/m2, p=0.002; late gadolinium enhancement (LGE) prevalence 52% vs 20%, pConclusionEF1 quantifies early, potentially reversible systolic dysfunction in aortic stenosis, is associated with global afterload and myocardial fibrosis, and is an independent predictor of AVR.

Background Previous studies suggest an association between short-term exposure to carbon monoxide and myocardial infarction. We performed a systematic review and meta-analysis to assess current evidence on this association to support the update of the World Health Organization (WHO) Global Air Quality Guidelines. Methods We searched Medline, Embase and Cochrane Central Register of Controlled Trials to update the evidence published in a previous systematic review up to 30th September 2018 for studies investigating the association between short-term exposure to ambient carbon monoxide (up to lag of seven days) and emergency department visits or hospital admissions and mortality due to myocardial infarction. Two reviewers assessed potentially eligible studies and performed data extraction independently. Random-effects meta-analysis was used to derive the pooled risk estimate per 1 mg/m3 increase in ambient carbon monoxide concentration. Risk of bias in individual studies was assessed using a domain-based assessment tool. The overall certainty of the body of evidence was evaluated using an adapted certainty of evidence assessment framework. Results We evaluated 1,038 articles from the previous review and our updated literature search, of which, 26 satisfied our inclusion criteria. Overall, myocardial infarction was associated with exposure to ambient carbon monoxide concentration (risk ratio of 1.052, 95% confidence interval 1.017–1.089 per 1 mg/m3 increase). A third of studies were assessed to be at high risk of bias (RoB) due to inadequate adjustment for confounding. Using an adaptation of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework, the overall evidence was assessed to be of moderate certainty. Conclusions This review demonstrated that the pooled risk ratio for myocardial infarction was 1.052 (95% CI 1.017–1.089) per 1 mg/m3 increase in ambient carbon monoxide concentration. However, very few studies originated from low- and middle-income countries.

Background Fibrosis is a fundamental process involved in healing and remodelling post myocardial infarction (MI) and during heart failure (HF). Positron emission tomography (PET) is a potential tool for investigating active collagen biosynthesis in the myocardium with fluoroprolines. We hypothesised that 18F-fluoroprolines can identify either triple helix collagen (trans-4-18F-fluoro-L-proline, e.g.scar tissue) or single-chain polypeptide abnormal collagen (cis 4 18F fluoro L proline, e.g.interstitial fibrosis) by directly targeting collagen biosynthesis. Methods Adult male Sprague-Dawley rats underwent total left coronary artery occlusion to induce MI. Seven days after MI, animals underwent magnetic resonance imaging (MRI) and were injected with trans- or cis-4-18F-fluoro-L-prolines for PET imaging. Hearts collected after in vivo imaging were stained with Picrosirius red (PSR) to assess myocardial fibrosis. Another set of rats underwent 4-week angiotensin-II (AngII) treatment (250 ng/kg/min or 500 ng/kg/min), to induce left ventricular hypertrophy and diffuse fibrosis, with blood pressure checks and ex vivo assessment of myocardial collagen content (PSR stain; hydroxyproline (HP) assay), to develop a model of interstitial fibrosis for future PET imaging studies. Results Uptake of trans-fluoroproline was strongest in the infarct area and cis-fluoroproline was strongest in the remote myocardium (mean standard uptake value ratio of 1.3 vs 0.7). The trans-fluoroproline SUVr strongly, and inversely correlated with ventricular ejection fraction (r2=0.93) and scar tissue size, as determined by MRI, and areas of fibrosis determined by PSR staining. Following AngII treatment, blood pressure significantly increased in both treatment groups by week 2 and stayed high until the end of the study in the high dose group compared to baseline. PSR analysis of heart tissue (AngII study-arm) showed a trend towards increased% fibrosis in the myocardium in the high dose group compared to controls. HP levels were significantly increased with high dose treatment compared to controls (mean: 0.7 vs 0.37 µg/mg; ANOVA p Conclusions Fluoroproline PET imaging could identify and quantify fibrosis activity in vivo following MI and the results validated with histological markers of fibrosis. Based on the results so far, the development of the diffuse fibrosis model to mimic hypertensive HF is promising. Future PET imaging studies with 18F-fluoroprolines and the model of hypertensive heart failure are ongoing.

Gadolinium chelates are widely used in cardiovascular magnetic resonance imaging (MRI) as passive intravascular and extracellular space markers. Manganese, a biologically active paramagnetic calcium analogue, provides novel intracellular myocardial tissue characterisation. We previously showed manganese-enhanced MRI (MEMRI) more accurately quantifies myocardial infarction than gadolinium delayed-enhancement MRI (DEMRI). Here, we evaluated the potential of MEMRI to assess myocardial viability compared to gold-standard 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) viability. Coronary artery ligation surgery was performed in male Sprague-Dawley rats (n = 13) followed by dual MEMRI and 18F-FDG PET imaging at 10–12 weeks. MEMRI was achieved with unchelated (EVP1001-1) or chelated (mangafodipir) manganese. T1 mapping MRI was followed by 18F-FDG micro-PET, with tissue taken for histological correlation. MEMRI and PET demonstrated good agreement with histology but native T1 underestimated infarct size. Quantification of viability by MEMRI, PET and MTC were similar, irrespective of manganese agent. MEMRI showed superior agreement with PET than native T1. MEMRI showed excellent agreement with PET and MTC viability. Myocardial MEMRI T1 correlated with 18F-FDG standard uptake values and influx constant but not native T1. Our findings indicate that MEMRI identifies and quantifies myocardial viability and has major potential for clinical application in myocardial disease and regenerative therapies.

Background Delayed-enhancement magnetic resonance imaging (DEMRI) with gadolinium detects macroscopic myocardial fibrosis, but does not directly assess myocardial function. Manganese, a paramagnetic calcium-analogue, enables direct dynamic assessment myocyte calcium handling and is a potential early marker of myocardial dysfunction. We have previously demonstrated manganese-enhanced MRI (MEMRI) can detect altered calcium-handling in remote remodelling myocardium in a rodent infarct model. Purpose To evaluate MEMRI as a marker of altered myocardial calcium handling in patients with non-ischaemic cardiomyopathy (NCT03607669). Methods Healthy volunteers (HV, n=20, 13 male, 42±11 years) and patients with hypertrophic (HCM, n=11, 5 male, 57±15 years) or dilated (DCM, n=5, 3 male, 56±14 years) cardiomyopathies underwent both DEMRI and MEMRI. Myocardial T1 was measured for 40 min after intravenous manganese dipyridoxyl diphosphate (Mn-DPDP, 5 μmol/kg) administration. Images were acquired at 3T with T1 imaging performed using Shortened Modified Look-Locker Inversion recovery [Figure A] (WIP #1048 Siemens Healthcare Ltd). Results No adverse effects were observed. In HV, the myocardialT1 profile following Mn-DPDP administration demonstrated a rapid initial descent (perfusion phase) followed by a slower, more gradual decrease which continued throughout the 40 min imaging period (mean reduction 25.2%, 283±9ms). In patients with HCM, T1 values followed a different pattern following Mn-DPDP administration. In areas of focal myocardial fibrosis (defined by DEMRI) there was again a sharp initial shortening of T1 but this was followed by a steady increase towards baseline, which eventually recovered to >40% of its initial value at 40 minutes. In areas of diffuse myocardial fibrosis, the initial shortening in the perfusion phase was followed by a more gradual recovery which then plateaued, remaining stable at 21% of native T1 by 40 min [Figure B]. Hypertrophied non-fibrosed myocardium had higher native T1 than HV (1178±45 vs 1133±36 ms P=0.005) and the rate of T1 reduction following the perfusion phase was slower (P=0.0005), leading to less overall T1 shortening at 40 min (880±40 vs 841±28 ms, P=0.004, [Figure C]). No patient with DCM had fibrosis by DEMRI. Native T1 was higher than HV (1234±26 vs 1133±36 ms, P MEMRI in non-ischaemic cardiomyopathy Conclusion MEMRI identifies altered calcium-handling in pathological myocardium of non-ischaemic cardiomyopathy, irrespective of fibrosis by DEMRI. This feasible, safe and novel method of functional myocardial tissue characterisation has exciting potential for future diagnostic, functional and clinical applications. Acknowledgement/Funding British Heart Foundation

Gadolinium chelates are widely used in cardiovascular magnetic resonance imaging (MRI) as passive intravascular and extracellular space markers. Manganese, a biologically active paramagnetic calcium analogue, provides novel intracellular myocardial tissue characterisation. We previously showed manganese-enhanced MRI (MEMRI) more accurately quantifies myocardial infarction than gadolinium delayed-enhancement MRI (DEMRI). Here, we evaluated the potential of MEMRI to assess myocardial viability compared to gold-standard 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) viability. Coronary artery ligation surgery was performed in male Sprague-Dawley rats (n = 13) followed by dual MEMRI and 18F-FDG PET imaging at 10–12 weeks. MEMRI was achieved with unchelated (EVP1001-1) or chelated (mangafodipir) manganese. T1 mapping MRI was followed by 18F-FDG micro-PET, with tissue taken for histological correlation. MEMRI and PET demonstrated good agreement with histology but native T1 underestimated infarct size. Quantification of viability by MEMRI, PET and MTC were similar, irrespective of manganese agent. MEMRI showed superior agreement with PET than native T1. MEMRI showed excellent agreement with PET and MTC viability. Myocardial MEMRI T1 correlated with 18F-FDG standard uptake values and influx constant but not native T1. Our findings indicate that MEMRI identifies and quantifies myocardial viability and has major potential for clinical application in myocardial disease and regenerative therapies.

Background Delayed-enhancement magnetic resonance imaging (DEMRI) using gadolinium overestimates infarct size acutely and indirectly estimates myocardial viability by quantifying scar burden. Manganese, an essential trace element and paramagnetic calcium-analogue (administered as chelated manganese dipyridoxyl diphosphate, MnDPDP), defines myocardial viability directly by imaging functional calcium-handling mechanisms. Our previous preclinical work demonstrated manganese-enhanced MRI (MEMRI) has potential to detect altered calcium-handling in remodelling myocardium following infarction. Purpose To assess whether MEMRI detects changes in myocardial calcium-handling after myocardial infarction (NCT03607669). Methods Healthy volunteers (HV, n=20, 13 male, 42±11 years) and patients with acute ST-segment elevation myocardial infarction with reduced ejection fraction (n=8, recruitment ongoing) underwent dual DEMRI and MEMRI, ≥48 hours apart, with T1 mapping. Patients returned for repeat imaging at 3 months. Myocardial T1 was measured every 2.5 min for 40 min after intravenous MnDPDP (5 umol/kg) administration. Images were acquired at 3T (Siemens Magnetom Skyrafit) with T1 imaging performed with Shortened Modified Look-Locker Inversion recovery (WIP #1048 Siemens Healthcare Ltd). Scanner-generated T1 maps are analysed to quantify T1 within regions of interest. Results No adverse effects were observed in any subject. In HV, MnDPDP rapidly reduced bloodpool T1 over 5 min (mean reduction 25.7%, 453±22 ms), followed by prompt normalisation to baseline by 40 min. Myocardial T1 also demonstrated a rapid initial descent (infusion phase) but this was followed by a slower, more gradual decrease which continued throughout the 40 min imaging period (mean reduction 25.2%, 283±9 ms) as evidence of Mn uptake by viable cardiomyocytes. In patients with acute myocardial infarction, the profile of myocardial T1 following MnDPDP was markedly different in the infarct compared to remote myocardium. In particular, areas of transmural infarction with microvascular obstruction demonstrated a recovery of T1 values similar to bloodpool (figure 1A), whilst T1 in regions of less extensive infarct plateaued after the infusion phase. In contrast to both, a sustained reduction was seen in the remote myocardium, similar to healthy volunteers. Three months post-myocardial infarction, two distinct T1 profiles were identifiable within the infarct zone (defined by DEMRI): (i) a central region demonstrating partial recovery of T1 following MnDPDP similar to microvascular obstruction and bloodpool, although less rapid, and (ii) the wider infarct region where T1 continued to decrease throughout the 40 min imaging period (figure 1B). This would suggest ongoing manganese uptake and viability despite near transmural late-enhancement (figure 1C), supported by improved wall thickening on cine imaging. Overall, T1 values at 40 min post-MnDPDP were 35.9% higher in regions of infarction compared to remote and healthy myocardium (1134±88 versus 843±28 ms, P 1050 ms, whereas remote and healthy myocardium had T1 Conclusion MEMRI of the myocardium with T1 mapping not only identifies myocardial infarction but also demarcates viability and delineates regions of viability within the infarct zone. This novel contrast imaging technique has exciting potential in ischaemic cardiomyopathy. Conflict of Interest None

We assessed myocardial calcium handling in patients with non-ischaemic cardiomyopathy usingmanganese-enhanced magnetic resonance imaging (MEMRI). Healthy volunteers (HV; n=20, 13 male, 42±11 yr), patients with hypertrophic (HCM; n=17, 10 male, 57±10 yr) or dilated (DCM; n=10, 6 male, 54±10 yr)

We assessed myocardial calcium handling in patients with acute and established myocardial withmanganese-enhanced magnetic resonance imaging (MEMRI). Patients (n=20) with acute myocardial infarction and healthy volunteers (n=20) underwent gadolinium delayed enhanced MRI (DEMRI) and MEMRI (

Myocardial fibrosis, identified by late gadolinium enhancement cardiovascular magnetic resonance, predicts outcomes in chronic heart failure (HF). Its prognostic significance in new-onset HF and reduced left ventricular ejection fraction (LVEF) is unclear. We investigated whether the pattern and extent of fibrosis predict survival in new-onset HF and reduced LVEF of initially uncertain pathogenesis.Of 120 consecutive patients with new-onset (6 months) HF and reduced LVEF, 31 (26%) had infarct fibrosis, 25 (21%) had midwall fibrosis, and 64 (53%) had no fibrosis. During median follow-up of 8.9 years, 33 (28%) patients died. Patients with infarct fibrosis (hazard ratios [HR], 3.32; 95% CI, 1.46-7.58; P=0.004) or midwall fibrosis (HR, 2.99; 95% CI, 1.24-7.19; P=0.014) were more likely to die compared with those without fibrosis. On multivariable analysis, the pattern and extent of fibrosis were both associated with all-cause mortality (by fibrosis pattern: infarct: HR, 2.60; 95% CI, 1.08-6.27; P=0.033; midwall: HR, 2.64; 95% CI, 1.08-6.47; P=0.034; by fibrosis extent per 1%: HR, 1.07; 95% CI, 1.03-1.12; P0.001). Fibrosis pattern also predicted composites of cardiovascular mortality or aborted sudden cardiac death (infarct: HR, 3.45; 95% CI, 1.20-9.90; P=0.022; midwall: HR, 6.59; 95% CI, 2.26-19.22; P0.001), and all-cause mortality, HF hospitalization, or aborted sudden cardiac death (infarct: HR, 2.69; 95% CI, 1.26-5.76; P=0.011; midwall fibrosis: HR, 2.97; 95% CI, 1.37-6.45; P=0.006). Addition of fibrosis pattern to LVEF improved risk prediction for all-cause mortality (LVEF versus LVEF+fibrosis C statistic: 0.66 versus 0.71; P=0.033). Importantly, the absence of fibrosis heralded a favorable prognosis with an 85% survival rate over the duration of follow-up.The pattern and extent of myocardial fibrosis predict adverse outcomes in new-onset HF and reduced LVEF. In contrast, the absence of fibrosis portends a durable warranty period with a low incidence of adverse events. These findings support a role for late gadolinium enhancement cardiovascular magnetic resonance in the early risk stratification of patients with HF of uncertain pathogenesis.

Background: Myocardial fibrosis, identified by late gadolinium enhancement cardiovascular magnetic resonance, predicts outcomes in chronic heart failure (HF). Its prognostic significance in new-onset HF and reduced left ventricular ejection fraction (LVEF) is unclear. We investigated whether the pattern and extent of fibrosis predict survival in new-onset HF and reduced LVEF of initially uncertain pathogenesis. Methods and Results: Of 120 consecutive patients with new-onset (P =0.004) or midwall fibrosis (HR, 2.99; 95% CI, 1.24–7.19; P =0.014) were more likely to die compared with those without fibrosis. On multivariable analysis, the pattern and extent of fibrosis were both associated with all-cause mortality (by fibrosis pattern: infarct: HR, 2.60; 95% CI, 1.08–6.27; P =0.033; midwall: HR, 2.64; 95% CI, 1.08–6.47; P =0.034; by fibrosis extent per 1%: HR, 1.07; 95% CI, 1.03–1.12; P P =0.022; midwall: HR, 6.59; 95% CI, 2.26–19.22; P P =0.011; midwall fibrosis: HR, 2.97; 95% CI, 1.37–6.45; P =0.006). Addition of fibrosis pattern to LVEF improved risk prediction for all-cause mortality (LVEF versus LVEF+fibrosis C statistic: 0.66 versus 0.71; P =0.033). Importantly, the absence of fibrosis heralded a favorable prognosis with an 85% survival rate over the duration of follow-up. Conclusions: The pattern and extent of myocardial fibrosis predict adverse outcomes in new-onset HF and reduced LVEF. In contrast, the absence of fibrosis portends a durable warranty period with a low incidence of adverse events. These findings support a role for late gadolinium enhancement cardiovascular magnetic resonance in the early risk stratification of patients with HF of uncertain pathogenesis.

Introduction Manganese-enhanced magnetic resonance imaging (MEMRI) is a promising non-invasive imaging tool in viability and cardiomyopathy, quantifying infarct size more accurately than late-gadolinium enhancement, as we previously demonstrated. We aimed to validate MEMRI viability against 18F-FDG positron emission tomography (PET). Methods Sprague-Dawley rats (male; 180–300 g) underwent permanent surgical anterior myocardial infarction (n=11), or sham surgery (n=2), with dual MEMRI and 18F-FDG PET assessment at 12 weeks. MEMRI (7 T spectrometer, Agilent, UK) was achieved with intravenous manganese gluconate (EVP1001–1, Eagle-Vision-Pharmaceuticals, USA; n=6, 22 μmol/kg) and mangafodipir (Teslascan, IC-Targets, Norway; n=7, 44 μmol/kg). Anatomical and functional imaging preceded cardiac-gated Modified Look-Locker Inversion recovery (MoLLI) before and 20 min post-contrast (at maximal infarct slice). Commercially available software generated standardised T1 maps for ROI-contouring. For PET imaging, intravenous 18F-FDG (20–30 MBq) was administered with PET data acquired for 60 min, followed by cardiac-gated acquisition (10 min). PET/MR images were co-registered and fused for analysis. Results Infarct size assessed by MEMRI T1 mapping was smaller than by native T1 at 12 weeks (mean 23.34 vs 18.68%; p=0.001). Native T1 mapping consistently overestimated infarct size (bias 25.76; 95% CI: 7.51 to 44.01; p=0.031) but there was excellent agreement between MEMRI T1 mapping and 18F-FDG (bias 1.30; 95% CI: −24.98 to 25.57; p=0.7). Post-MEMRI T1 values showed negative trend with increasing SUV (r2=0.25, p=0.08) whereas native T1 demonstrated no relationship (r2=0.0001, p>0.9). Conclusion MEMRI T1 mapping identifies viable myocardium as well as 18F-FDG PET and was superior to native T1 mapping. Post-MEMRI T1 appears related to SUV where native T1 does not. This validation data informs the clinical translation of cardiac MEMRI.

Introduction There is interest in measures of myocardial health in aortic stenosis (AS) to identify left ventricular (LV) decompensation and optimise timing of surgical intervention. CMR global longitudinal strain (GLS) is increasingly explored. We investigated the relationship of CMR GLS with established markers of AS severity, myocardial fibrosis and clinical outcomes. Methods CMRs from AS patients (n=159) and healthy controls (n=42) were analysed using commercially available software. LV contours were drawn (long and short-axis cines). Automated analysis calculated 2D and 3D strain. Myocardial fibrosis was assessed using T1-mapping and late-gadolinium enhancement (LGE). Mortality was assessed at 1,466 days (median). Statistical analysis planning was published prior. Results 2D-LVGLS correlated with AS severity (Vmax;r=0.24;p=0.0005), ejection fraction (EF, r=−0.33; p Conclusion CMR 2D-LVGLS measured may be a functional manifestation of myocardial fibrosis and LV decompensation in AS. However, substantial overlap between groups was observed and 2D-LVGLS did not predict clinical outcomes.

Ultrasmall superparamagnetic particles of iron oxide (USPIO)-enhanced MRI can detect tissue-resident macrophage activity and identify cellular inflammation within tissues. We hypothesised that USPIO-enhanced MRI would provide a non-invasive imaging technique that would improve the diagnosis and management of patients with acute myocarditis.Ten volunteers and 14 patients with suspected acute myocarditis underwent T2, T2* and late gadolinium enhancement (LGE) 3T MRI, with further T2* imaging at 24 hours after USPIO (ferumoxytol, 4 mg/kg) infusion, at baseline and 3 months. Myocardial oedema and USPIO enhancement were determined within areas of LGE as well as throughout the myocardium.Myocarditis was confirmed in nine of the 14 suspected cases of myocarditis. There was greater myocardial oedema in regions of LGE in patients with myocarditis when compared with healthy volunteer myocardium (T2 value, 57.1±5.3 vs 46.7±1.6 ms, p0.0001). There was no demonstrable difference in USPIO enhancement between patients and volunteers even within regions displaying LGE (change in R2*, 35.0±15.0 vs 37.2±9.6 sIn patients with acute myocarditis, USPIO-enhanced MRI does not provide additional clinically relevant information to LGE and T2 mapping MRI. This suggests that tissue-resident macrophages do not provide a substantial contribution to the myocardial inflammation in this condition.Clinical trial registration NCT02319278; Results.

PURPOSE: To use global longitudinal strain (GLS) as a marker of left ventricular decompensation in aortic stenosis and to investigate the relationship of GLS measured with cardiac MRI with markers of myocardial fibrosis, symptom development, remodeling, and clinical outcomes. MATERIALS AND METHODS: Patients with aortic stenosis and healthy control subjects were assessed. GLS was assessed by using cardiac MRI feature tracking, diffuse fibrosis by T1 mapping, and replacement fibrosis using late gadolinium enhancement. Follow-up was prospective for the primary endpoint of all-cause mortality. RESULTS: GLS was reduced in aortic stenosis (n = 159) compared with control subjects (n = 41) (−17.6% ± 3.1 [standard deviation] vs −18.9% ± 2.6, P = .02). GLS demonstrated weak associations with aortic stenosis severity (V(max); r = 0.24, P = .0005) but showed moderate correlation with T1 mapping measures of myocardial fibrosis (eg, indexed extracellular volume [iECV]; r = 0.43, P < .0001). Moreover, GLS was reduced in patients with midwall fibrosis compared with control subjects (P < .001), although values were similar to those of patients with myocardial infarction (P = .25). In adjusted analyses, GLS was associated with total myocardial fibrosis burden (iECV) and ejection fraction (both P < .001). GLS offered poor discrimination between disease states, inability to distinguish between control subjects and patients (area under the curve [AUC], 0.60), presence or absence of fibrosis (AUC, 0.63), or symptomatic severity (left ventricular decompensation AUC, 0.64). At follow-up (median, 1466 days), 21 patients died. GLS did not independently predict clinical outcomes. CONCLUSION: GLS correlates with established markers of myocardial fibrosis. However, widespread utility of single GLS measurements may be limited by overlap between disease states and its inability to predict clinical outcomes beyond current established markers. © RSNA, 2019 Supplemental material is available for this article.