ATP derived from the conversion of phosphocreatine to creatine by creatine kinase provides an essential chemical energy source that governs myocardial contraction. Here, we demonstrate that the exchange of amine protons from creatine with protons in bulk water can be exploited to image creatine through chemical exchange saturation transfer (CrEST) in myocardial tissue. We show that CrEST provides about two orders of magnitude higher sensitivity compared to 1H magnetic resonance spectroscopy. Results of CrEST studies from ex vivo myocardial tissue strongly correlate with results from 1H and 31P magnetic resonance spectroscopy and biochemical analysis. We demonstrate the feasibility of CrEST measurement in healthy and infarcted myocardium in animal models in vivo on a 3-T clinical scanner. As proof of principle, we show the conversion of phosphocreatine to creatine by spatiotemporal mapping of creatine changes in the exercised human calf muscle. We also discuss the potential utility of CrEST in studying myocardial disorders.
Background Injectable, acellular biomaterials hold promise to limit left ventricular (LV) remodeling and heart failure precipitated by infarction through bulking and/or stiffening the infarct region. A material with tunable properties (e.g., mechanics, degradation) that can be delivered percutaneously has not yet been demonstrated. Catheter deliverable soft hydrogels with in vivo stiffening to enhance therapeutic efficacy achieve these requirements. Methods and Results We developed a hyaluronic acid hydrogel that utilizes a tandem crosslinking approach, where the first crosslinking (guest-host, GH) enabled injection and localized retention of a soft (<1kPa) hydrogel. A second crosslinking reaction (dual-crosslinking, DC) stiffened the hydrogel (41.4±4.3kPa) after injection. Posterolateral infarcts were investigated in an ovine model (n≥6 per group), with injection of saline (MI control), GH, or DC. Computational (day 1), histological (1 day, 8 wk), morphological and functional (0, 2, 8 wk) outcomes were evaluated. Finite element modeling projected myofiber stress reduction (>50%, P<0.001) with DC but not GH injection. Remodeling, assessed by infarct thickness and LV volume, was mitigated by hydrogel treatment. Ejection fraction was improved, relative to MI at 8 weeks, with DC (37% improvement, P=0.014) and GH (15% improvement, P=0.058) treatments. Percutaneous delivery via endocardial injection was investigated with fluoroscopic and echocardiographic guidance, with delivery visualized by MRI. Conclusions A percutaneous delivered hydrogel system was developed, and hydrogels with increased stiffness were most effective in ameliorating LV remodeling and preserving function. Ultimately, engineered systems such as these have the potential to provide effective clinical options to limit remodeling in patients after infarction.
BackgroundLate gadolinium enhanced (LGE) cardiovascular magnetic resonance (CMR) is frequently used to evaluate myocardial viability, estimate total infarct size and transmurality, but is not always straightforward is and contraindicated in patients with renal failure because of the risk of nephrogenic systemic fibrosis. T2- and T1-weighted CMR alone is however relatively insensitive to chronic myocardial infarction (MI) in the absence of a contrast agent. The objective of this manuscript is to explore T1ρ-weighted rotating frame CMR techniques for infarct characterization without contrast agents. We hypothesize that T1ρ CMR accurately measures infarct size in chronic MI on account of a large change in T1ρ relaxation time between scar and myocardium.Methods7Yorkshire swine underwent CMR at 8 weeks post-surgical induction of apical or posterolateral myocardial infarction. Late gadolinium enhanced and T1ρ CMR were performed at high resolution to visualize MI. T1ρ-weighted imaging was performed with a B1 = 500 Hz spin lock pulse on a 3 T clinical MR scanner. Following sacrifice, the heart was excised and infarct size was calculated by optical planimetry. Infarct size was calculated for all three methods (LGE, T1ρ and planimetry) and statistical analysis was performed. T1ρ relaxation time maps were computed from multiple T1ρ-weighted images at varying spin lock duration.ResultsMean infarct contrast-to-noise ratio (CNR) in LGE and T1ρ CMR was 2.8 ± 0.1 and 2.7 ± 0.1. The variation in signal intensity of tissues was found to be, in order of decreasing signal intensity, LV blood, fat and edema, infarct and healthy myocardium. Infarct size measured by T1ρ CMR (21.1% ± 1.4%) was not significantly different from LGE CMR (22.2% ± 1.5%) or planimetry (21.1% ± 2.7%; p < 0.05).T1ρ relaxation times were T1ρinfarct = 91.7 ms in the infarct and T1ρremote = 47.2 ms in the remote myocardium.ConclusionsT1ρ-weighted imaging using long spin locking pulses enables high discrimination between infarct and myocardium. T1ρ CMR may be useful to visualizing MI without the need for exogenous contrast agents for a wide range of clinical cardiac applications such as to distinguish edema and scar tissue and tissue characterization of myocarditis and ventricular fibrosis.
T1r relaxation times were quantified in a swine model of chronic, left ventricular myocardial infarction. It was found that there were low frequency relaxation mechanisms that suppress endogenous contrast at low spin-lock amplitudes and in T2-weighted images. A moderate amplitude spin-locking pulse could overcome these relaxation mechanisms. Relaxation dispersion data were measured over a range of RF field amplitudes, and a model was formulated to include dipole-dipole relaxation modulated by molecular rotation and an apparent exchange mechanism. These techniques may find some use in the clinic for the observation of chronic, left ventricular cardiac remodeling. Magn Reson Med 64:1454-1461,
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