Abstract
Background Manganese-enhanced MRI (MEMRI) has the potential to identify viable myocardium and quantify calcium influx and handling. Two distinct manganese contrast media have been developed for clinical application, mangafodipir and EVP1001-1, employing different strategies to mitigate against adverse effects resulting from calcium-channel agonism. Mangafodipir delivers manganese ions as a chelate, and EVP1001-1 coadministers calcium gluconate. Using myocardial T1 mapping, we aimed to explore chelated and nonchelated manganese contrast agents, their mechanism of myocardial uptake, and their application to infarcted hearts. Methods T1 mapping was performed in healthy adult male Sprague-Dawley rats using a 7T MRI scanner before and after nonchelated (EVP1001-1 or MnCl2 (22 μmol/kg)) or chelated (mangafodipir (22–44 μmol/kg)) manganese-based contrast media in the presence of calcium channel blockade (diltiazem (100–200 μmol/kg/min)) or sodium chloride (0.9%). A second cohort of rats underwent surgery to induce anterior myocardial infarction by permanent coronary artery ligation or sham surgery. Infarcted rats were imaged with standard gadolinium delayed enhancement MRI (DEMRI) with inversion recovery techniques (DEMRI inversion recovery) as well as DEMRI T1 mapping. A subsequent MEMRI scan was performed 48 h later using either nonchelated or chelated manganese and T1 mapping. Finally, animals were culled at 12 weeks, and infarct size was quantified histologically with Masson's trichrome (MTC). Results Both manganese agents induced concentration-dependent shortening of myocardial T1 values. This was greatest with nonchelated manganese, and could be inhibited by 30–43% with calcium-channel blockade. Manganese imaging successfully delineated the area of myocardial infarction. Indeed, irrespective of the manganese agent, there was good agreement between infarct size on MEMRI T1 mapping and histology (bias 1.4%, 95% CI −14.8 to 17.1 P>0.05). In contrast, DEMRI inversion recovery overestimated infarct size (bias 11.4%, 95% CI −9.1 to 31.8 P=0.002), as did DEMRI T1 mapping (bias 8.2%, 95% CI −10.7 to 27.2 P=0.008). Increased manganese uptake was also observed in the remote myocardium, with remote myocardial ∆T1 inversely correlating with left ventricular ejection fraction after myocardial infarction (r=−0.61, P=0.022). Conclusions MEMRI causes concentration and calcium channel-dependent myocardial T1 shortening. MEMRI with T1 mapping provides an accurate assessment of infarct size and can also identify changes in calcium handling in the remote myocardium. This technique has potential applications for the assessment of myocardial viability, remodelling, and regeneration.
Highlights
With major and sustained advances in imaging techniques over the past 3 decades, magnetic resonance imaging (MRI), along with other advanced modalities such as positron emission tomography (PET), has become an essential element to noninvasive structural and functional cardiac imaging [1,2,3]
Discussion e present study applies myocardial T1 mapping to manganese-enhanced MRI, in healthy myocardium in addition to remote myocardium after infarction. is novel combination of imaging techniques has been employed to directly compare two distinct manganese contrast agents with conventional delayed enhancement MRI (DEMRI) in the assessment of viability by infarct size, as well as examine altered calcium handling in remodelling myocardium over time, building on previous pilot data in myocardial infarction. is work was designed as a precursor to clinical translation of intramyocardial contrast imaging, for development of this promising eld within cardiac MRI which has potential to improve accuracy of myocardial viability assessment, improve understanding of pathophysiology, and monitor response to therapy in di erent forms of cardiomyopathy
We have demonstrated that Manganese-enhanced MRI (MEMRI) causes an ionic, concentration, and calcium channel-dependent shortening of myocardial T1 values
Summary
With major and sustained advances in imaging techniques over the past 3 decades, magnetic resonance imaging (MRI), along with other advanced modalities such as positron emission tomography (PET), has become an essential element to noninvasive structural and functional cardiac imaging [1,2,3]. Current standard clinical methods use inversion recovery-delayed enhancement sequences after gadoliniumbased contrast administration to image myocardial scar. Quantification by gadolinium delayed enhancement MRI (DEMRI) is subject to overestimation of acute infarct size due to tissue oedema [7]. It is associated with imaging artefact and interpretation bias in challenging patient populations. T1 mapping was performed in healthy adult male Sprague-Dawley rats using a 7T MRI scanner before and after nonchelated (EVP1001-1 or MnCl2 (22 μmol/kg)) or chelated (mangafodipir (22–44 μmol/kg)) manganese-based contrast media in the presence of calcium channel blockade (diltiazem (100–200 μmol/kg/min)) or sodium chloride (0.9%). MEMRI with T1 mapping provides an accurate assessment of infarct size and can identify changes in calcium handling in the remote myocardium. is technique has potential applications for the assessment of myocardial viability, remodelling, and regeneration
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