Myocardial infarction (MI) produces acute changes in strain and stiffness within the infarct that can affect remote areas of the left ventricle (LV) and drive pathological remodeling. We hypothesized ...that intramyocardial delivery of a hydrogel within the MI region would lower wall stress and reduce adverse remodeling in Yorkshire pigs (n = 5). 99mTc-Tetrofosmin SPECT imaging defined the location and geometry of induced MI and border regions in pigs, and in vivo and ex vivo contrast cine computed tomography (cineCT) quantified deformations of the LV myocardium. Serial in vivo cineCT imaging provided data in hearts from control pigs (n = 3) and data from pigs (n = 5) under baseline conditions before MI induction, post-MI day 3, post-MI day 7, and one hour after intramyocardial delivery of a hyaluronic acid (HA)-based hydrogel with shear-thinning and self-healing properties to the central infarct area. Isolated, excised hearts underwent similar cineCT imaging using an ex vivo perfused heart preparation with cyclic LV pressurization. Deformations were evaluated using nonlinear image registration of cineCT volumes between end-diastole (ED) and end-systole (ES), and 3D Lagrangian strains were calculated from the displacement gradients. Post-MI day 3, radial, circumferential, maximum principal, and shear strains were reduced within the MI region (p < 0.04) but were unchanged in normal regions (p > 0.6), and LV end diastolic volume (LV EDV) increased (p = 0.004), while ejection fraction (EF) and stroke volume (SV) decreased (p < 0.02). Post-MI day 7, radial strains in MI border zones increased (p = 0.04) and dilation of LV EDV continued (p = 0.052). There was a significant negative linear correlation between regional radial and maximum principal/shear strains and percent infarcted tissue in all hearts (R2 > 0.47, p < 0.004), indicating that cineCT strain measures could predict MI location and degree of injury. Post-hydrogel day 7 post-MI, LV EDV was significantly reduced (p = 0.009), EF increased (p = 0.048), and radial (p = 0.021), maximum principal (p = 0.051), and shear strain (p = 0.047) increased within regions bordering the infarct. A smaller strain improvement within the infarct and normal regions was also noted on average along with an improvement in SV in 4 out of 5 hearts. CineCT provides a reliable method to assess regional changes in strains post-MI and the therapeutic effects of intramyocardial hydrogel delivery.
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•Developed novel platform to assess left ventricle deformation in vivo and ex vivo.•Local cardiac strains decreased progressively over 7 days in infarcted regions.•Measured linear correlation between local degree of infarction and strain.•Hydrogel injection improved strain in regions bordering the infarct.•Hydrogel injection resulted in less ventricle dilation and larger ejection fraction.
The insertion of a stent in diseased arteries is a common endovascular procedure that can be compromised by the development of short- and long-term inflammatory responses leading to restenosis and ...thrombosis, respectively. While treatment with drugs, either systemic or localized, has decreased the incidence of restenosis and thrombosis these complications persist and are associated with a high mortality in those that present with stent thrombosis. We reasoned that if stents could be made to undergo accelerated endothelialization in the deployed region, then such an approach would further decrease the occurrence of stent thrombosis and restenosis thereby improving clinical outcomes. Toward that objective, the first step necessitated efficient capture of progenitor stem cells, which eventually would become the new endothelium. To achieve this objective, we engineered intrinsic ferromagnetism within nonmagnetizable, biodegradable magnesium (Mg) bare metal stents. Mg stents were coated with biodegradable polylactide (PLA) polymer embedding magnetizable iron–platinum (FePt) alloy nanoparticles, nanomagnetic particles, nMags, which increased the surface area and hence magnetization of the stent. nMags uniformly distributed on stents enabled capture, under flow, up to 50 mL/min, of systemically injected iron-oxide-labeled (IO-labeled) progenitor stem cells. Critical parameters enhancing capture efficiency were optimized, and we demonstrated the generality of the approach by showing that nMag-coated stents can capture different cell types. Our work is a potential paradigm shift in engineering stents because implants are rendered as tissue in the body, and this “natural stealthiness” reduces or eliminates issues associated with pro-inflammatory immune responses postimplantation.
The quantitative estimation of regional cardiac deformation from three-dimensional (3-D) image sequences has important clinical implications for the assessment of viability in the heart wall. We ...present here a generic methodology for estimating soft tissue deformation which integrates image-derived information with biomechanical models, and apply it to the problem of cardiac deformation estimation. The method is image modality independent. The images are segmented interactively and then initial correspondence is established using a shape-tracking approach. A dense motion field is then estimated using a transversely isotropic, linear-elastic model, which accounts for the muscle fiber directions in the left ventricle. The dense motion field is in turn used to calculate the deformation of the heart wall in terms of strain in cardiac specific directions. The strains obtained using this approach in open-chest dogs before and after coronary occlusion, exhibit a high correlation with strains produced in the same animals using implanted markers. Further, they show good agreement with previously published results in the literature. This proposed method provides quantitative regional 3-D estimates of heart deformation.
Objective/Background To evaluate the feasibility and repeatability of applying blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) in the feet to quantify regional dynamic changes in ...tissue oxygenation during proximal cuff occlusion and reactive hyperemia. Methods Ten healthy male subjects underwent BOLD and T1-weighted imaging of the feet on two separate occasions, using a 3-T scanner. Dynamic changes in BOLD signal intensity were assessed before and during proximal cuff occlusion of the thigh and during reactive hyperemia, and BOLD time course data were evaluated for the time-to-half ischemic minimum, minimum ischemic value, peak hyperemic value, time-to-peak hyperemia, time-to-half peak hyperemia, and end value. T1-weighted images were used for segmentation of volumes of interest (VOI) in anatomical regions of the foot (heel, toes, dorsal foot, medial and lateral plantar foot). Repeatability of vascular responses was assessed for each foot VOI using semiautomated image registration and quantification of serial BOLD images. Results The heel VOI demonstrated a significantly higher peak hyperemic response, expressed as percent change from baseline BOLD signal intensity, compared with all other VOIs of the foot (heel, 7.4 ± 1.2%; toes, 5.6 ± 0.8%; dorsal foot, 5.7 ± 1.6%; medial plantar, 5.6 ± 1.7%; lateral plantar, 5.6 ± 1.5% p < .05). Additionally, the lateral plantar VOI had a significantly lower terminal signal intensity value (i.e., end value) when compared with all foot VOIs ( p < .05). BOLD MRI was repeatable between visits in all foot VOIs, with no significant differences between study visits for any of the evaluated functional indices. Conclusion BOLD MRI offers a repeatable technique for volumetric assessment of regional foot tissue oxygenation. Future application of BOLD imaging in the feet of patients with peripheral vascular disease may permit serial evaluation of regional tissue oxygenation and allow for improved assessment of therapeutic interventions targeting specific sites of the foot.
Noninvasive imaging strategies will be critical for defining the temporal characteristics of angiogenesis and assessing efficacy of angiogenic therapies. The alphavbeta3 integrin is expressed in ...angiogenic vessels and represents a potential novel target for imaging myocardial angiogenesis. We demonstrated the localization of an indium-111-labeled ((111)In-labeled) alphavbeta3-targeted agent in the region of injury-induced angiogenesis in a chronic rat model of infarction. The specificity of the targeted alphavbeta3-imaging agent for angiogenesis was established using a nonspecific control agent. The potential of this radiolabeled alphavbeta3-targeted agent for in vivo imaging was then confirmed in a canine model of postinfarction angiogenesis. Serial in vivo dual-isotope single-photon emission-computed tomographic (SPECT) imaging with the (111)In-labeled alphavbeta3-targeted agent demonstrated focal radiotracer uptake in hypoperfused regions where angiogenesis was stimulated. There was a fourfold increase in myocardial radiotracer uptake in the infarct region associated with histological evidence of angiogenesis and increased expression of the alphavbeta3 integrin. Thus, angiogenesis in the heart can be imaged noninvasively with an (111)In-labeled alphavbeta3-targeted agent. The noninvasive evaluation of angiogenesis may have important implications for risk stratification of patients following myocardial infarction. This approach may also have significant clinical utility for noninvasively tracking therapeutic myocardial angiogenesis.
Abstract Purpose Coronary microvascular dysfunction (CMD) is a common but underdiagnosed cause of chest pain. Literature is scant regarding effective treatments. We explored the effect of ranolazine ...on coronary flow reserve (CFR) among symptomatic patients with CMD. Methods This pilot double-blinded randomized controlled trial included emergency department patients with chest pain and CMD admitted to an observation unit between June 2014 and November 2015. Participants were assessed by cardiac Rb-82 positron emission tomography and computed tomography imaging at baseline and 30 days. CMD was defined as CFR <2 corrected for rate pressure product or <2.5 uncorrected, with no evidence of obstructive or nonobstructive coronary artery disease or calcification. Patients with infarction, hypertensive urgency, heart failure, or prescribed QTc-prolonging drugs were excluded. Participants were assigned to ranolazine or placebo in a 2:1 ratio. Primary outcome was change in CFR at 30 days. Findings We enrolled 31 patients (71% female, mean SD age 50 6 years) with CMD (mean SD corrected CFR 1.6 0.3). Ranolazine improved CFR at 30 days by 17% ( P = 0.005) compared with 0% with placebo ( P = 0.67). However, there was no significant difference in the primary outcome as measured by mean change in CFR (0.27 ranolazine compared with 0.06 placebo; 95% CI, −0.08 to 0.62). Implications The emergency department offers a unique venue to diagnose CMD with acute symptoms. In an exploratory randomized controlled trial of symptomatic patients with CMD and no coronary artery disease, promising results were seem with ranolazine and CFR improving at 30 days. Large robust clinical trials are needed to verify improvement of CMD in a sex-specific model. ClinicalTrials.gov identifier NCT02052011.
A healthy, functional microcirculation in combination with nonobstructed epicardial coronary arteries is the prerequisite of normal myocardial perfusion. Quantitative assessment in myocardial ...perfusion and determination of absolute myocardial blood flow can be achieved noninvasively using dynamic imaging with multiple imaging modalities. Extensive evidence supports the clinical value of noninvasively assessing indices of coronary flow for diagnosing coronary microvascular dysfunction; in certain diseases, the degree of coronary microvascular impairment carries important prognostic relevance. Although, currently positron emission tomography is the most commonly used tool for the quantification of myocardial blood flow, other modalities, including single-photon emission computed tomography, computed tomography, magnetic resonance imaging, and myocardial contrast echocardiography, have emerged as techniques with great promise for determination of coronary microvascular dysfunction. The following review will describe basic concepts of coronary and microvascular physiology, review available modalities for dynamic imaging for quantitative assessment of coronary perfusion and myocardial blood flow, and discuss their application in distinct forms of coronary microvascular dysfunction.
Proposes and validates the hypothesis that one can use differential shape properties of the myocardial surfaces to recover dense field motion from standard three-dimensional (3-D) image sequences ...(MRI and CT). Quantitative measures of left ventricular regional function can be further inferred from the point correspondence maps. The noninvasive, algorithm-derived results are validated on two levels. First, the motion trajectories are compared to those of implanted imaging-opaque markers of a canine model in two imaging modalities, where subpixel accuracy is achieved. Second, the validity of using motion parameters (path length and thickness changes) for detecting myocardial injury area is tested by comparing algorithms derived results to postmortem analysis TTC staining of myocardial tissue, where the achieved Pearson product-moment correlation value is 0.968.
Time-dependent activation of matrix metalloproteinases (MMPs) after myocardial infarction (MI) contributes to adverse left ventricular (LV) remodeling; however, noninvasive methods to monitor this ...process serially are needed.
MMP-targeted radiotracers were developed that displayed selective binding kinetics to the active MMP catalytic domain. Initial nonimaging studies were performed with a (111)In-labeled MMP-targeted radiotracer ((111)In-RP782) and negative control compound ((111)In-RP788) in control mice (Ctrl) and in mice 1 week after surgically induced MI. Localization of (111)In-RP782 was demonstrated within the MI by microautoradiography. A 334+/-44% increase (P<0.001 versus Ctrl) in relative retention of (111)In-RP782 was confirmed by gamma well counting of myocardium. Subsequent high-resolution dual-isotope planar and hybrid micro-single-photon emission computed tomography/CT imaging studies with an analogous 99mTc-labeled MMP-targeted radiotracer (99mTc-RP805) and 201Tl demonstrated favorable biodistribution and clearance kinetics of 99mTc-RP805 for in vivo cardiac imaging, with robust retention 1 to 3 weeks after MI in regions of decreased 201Tl perfusion. Gamma well counting yielded a similar approximately 300% increase in relative myocardial retention of 99mTc-RP805 in MI regions (Ctrl, 102+/-9%; 1 week, 351+/-77%; 2 weeks, 291+/-45%; 3 weeks, 292+/-41%; P<0.05 versus Ctrl). Myocardial uptake in the MI region was also significantly increased approximately 5-fold when expressed as percentage injected dose per gram tissue. There was also a significant 2-fold increase in myocardial activity in remote regions relative to control mice, suggesting activation of MMPs in regions remote from the MI.
This novel noninvasive targeted MMP radiotracer imaging approach holds significant diagnostic potential for in vivo localization of MMP activation and tracking of MMP-mediated post-MI remodeling.
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