Orlando P. Simonetti

Atrial fibrillation driven by micro-anatomic intramural re-entry revealed by simultaneous sub-epicardial and sub-endocardial optical mapping in explanted human hearts

AIMSnThe complex architecture of the human atria may create physical substrates for sustained re-entry to drive atrial fibrillation (AF). The existence of sustained, anatomically defined AF drivers in humans has been challenged partly due to the lack of simultaneous endocardial-epicardial (Endo-Epi) mapping coupled with high-resolution 3D structural imaging.nnnMETHODS AND RESULTSnCoronary-perfused human right atria from explanted diseased hearts (n = 8, 43-72 years old) were optically mapped simultaneously by three high-resolution CMOS cameras (two aligned Endo-Epi views (330 µm2 resolution) and one panoramic view). 3D gadolinium-enhanced magnetic resonance imaging (GE-MRI, 80 µm3 resolution) revealed the atrial wall structure varied in thickness (1.0 ± 0.7-6.8 ± 2.4 mm), transmural fiber angle differences, and interstitial fibrosis causing transmural activation delay from 23 ± 11 to 43 ± 22 ms at increased pacing rates. Sustained AF (>90 min) was induced by burst pacing during pinacidil (30-100 µM) perfusion. Dual-sided sub-Endo-sub-Epi optical mapping revealed that AF was driven by spatially and temporally stable intramural re-entry with 107 ± 50 ms cycle length and transmural activation delay of 67 ± 31 ms. Intramural re-entrant drivers were captured primarily by sub-Endo mapping, while sub-Epi mapping visualized re-entry or breakthrough patterns. Re-entrant drivers were anchored on 3D micro-anatomic tracks (15.4 ± 2.2 × 6.0 ± 2.3 mm2, 2.9 ± 0.9 mm depth) formed by atrial musculature characterized by increased transmural fiber angle differences and interstitial fibrosis. Targeted radiofrequency ablation of the tracks verified these re-entries as drivers of AF.nnnCONCLUSIONSnIntegrated 3D structural-functional mapping of diseased human right atria ex vivo revealed that the complex atrial microstructure caused significant differences between Endo vs. Epi activation during pacing and sustained AF driven by intramural re-entry anchored to fibrosis-insulated atrial bundles.

Three-dimensional integrated functional, structural, and computational mapping to define the structural "fingerprints" of heart-specific atrial fibrillation drivers in human heart ex vivo

Background Structural remodeling of human atria plays a key role in sustaining atrial fibrillation (AF), but insufficient quantitative analysis of human atrial structure impedes the treatment of AF. We aimed to develop a novel 3‐dimensional (3D) structural and computational simulation analysis tool that could reveal the structural contributors to human reentrant AF drivers. Methods and Results High‐resolution panoramic epicardial optical mapping of the coronary‐perfused explanted intact human atria (63‐year‐old woman, chronic hypertension, heart weight 608 g) was conducted during sinus rhythm and sustained AF maintained by spatially stable reentrant AF drivers in the left and right atrium. The whole atria (107×61×85 mm3) were then imaged with contrast‐enhancement MRI (9.4 T, 180×180×360‐μm3 resolution). The entire 3D human atria were analyzed for wall thickness (0.4–11.7 mm), myofiber orientations, and transmural fibrosis (36.9% subendocardium; 14.2% midwall; 3.4% subepicardium). The 3D computational analysis revealed that a specific combination of wall thickness and fibrosis ranges were primarily present in the optically defined AF driver regions versus nondriver tissue. Finally, a 3D human heart–specific atrial computer model was developed by integrating 3D structural and functional mapping data to test AF induction, maintenance, and ablation strategies. This 3D model reproduced the optically defined reentrant AF drivers, which were uninducible when fibrosis and myofiber anisotropy were removed from the model. Conclusions Our novel 3D computational high‐resolution framework may be used to quantitatively analyze structural substrates, such as wall thickness, myofiber orientation, and fibrosis, underlying localized AF drivers, and aid the development of new patient‐specific treatments.

Novel application of 3D contrast-enhanced CMR to define fibrotic structure of the human sinoatrial node in vivo

AimsnThe adult human sinoatrial node (SAN) has a specialized fibrotic intramural structure (35-55% fibrotic tissue) that provides mechanical and electrical protection from the surrounding atria. We hypothesize that late gadolinium-enhanced cardiovascular magnetic resonance (LGE-CMR) can be applied to define the fibrotic human SAN structure in vivo.nnnMethods and results nLGE-CMR atrial scans of healthy volunteers (nu2009olu, 23-52 y.o.) using a 3 Tesla magnetic resonance imaging system with a spatial resolution of 1.0u2009mm3 or 0.625 × 0.625 × 1.25u2009mm3 were obtained and analysed. Percent fibrosis of total connective and cardiomyocyte tissue area in segmented atrial regions were measured based on signal intensity differences of fibrotic vs. non-fibrotic cardiomyocyte tissue. A distinct ellipsoidal fibrotic region (length: 23.6u2009±u20091.9u2009mm; width: 7.2u2009±u20090.9u2009mm; depth: 2.9u2009±u20090.4u2009mm) in all hearts was observed along the posterior junction of the crista terminalis and superior vena cava extending towards the interatrial septum, corresponding to the anatomical location of the human SAN. The SAN fibrotic region consisted of 41.9u2009±u20095.4% of LGE voxels above an average threshold of 2.7 SD (range 2-3 SD) from the non-fibrotic right atrial free wall tissue. Fibrosis quantification and SAN identification by in vivo LGE-CMR were validated in optically mapped explanted donor hearts ex vivo (nu2009ivo, 19-65 y.o.) by contrast-enhanced CMR (9.4 Tesla; up to 90 µm3 resolution) correlated with serial histological sections of the SAN.nnnConclusionnThis is the first study to visualize the 3D human SAN fibrotic structure in vivo using LGE-CMR. Identification of the 3D SAN location and its high fibrotic content by LGE-CMR may provide a new tool to avoid or target SAN structure during ablation.

Rapid assessment of quantitative T1, T2 and T2* in lower extremity muscles in response to maximal treadmill exercise

MRI provides a non‐invasive diagnostic platform to quantify the physical and physiological attributes of skeletal muscle at rest and in response to exercise. MR relaxation parameters (T1, T2 and T2*) are characteristic of tissue composition and metabolic properties. With the recent advent of quantitative techniques that allow rapid acquisition of T1, T2 and T2* maps, we posited that an integrated treadmill exercise–quantitative relaxometry paradigm can rapidly characterize exercise‐induced changes in skeletal muscle relaxation parameters. Accordingly, we investigated the rest/recovery kinetics of T1, T2 and T2* in response to treadmill exercise in the anterior tibialis, soleus and gastrocnemius muscles of healthy volunteers, and the relationship of these parameters to age and gender. Thirty healthy volunteers (50.3 ± 16.6 years) performed the Bruce treadmill exercise protocol to maximal exhaustion. Relaxometric maps were sequentially acquired at baseline and for approximately 44 minutes post‐exercise. Our results show that T1, T2 and T2* are significantly and differentially increased immediately post‐exercise among the leg muscle groups, and these values recover to near baseline within 30–44 minutes. Our results demonstrate the potential to characterize the kinetics of relaxation parameters with quantitative mapping and upright exercise, providing normative values and some clarity on the impact of age and gender. Copyright

Free-breathing myocardial T2* mapping using GRE-EPI and automatic Non-rigid motion correction

BackgroundMeasurement of myocardial T2* is becoming widely used in the assessment of patients at risk for cardiac iron overload. The conventional breath-hold, ECG-triggered, segmented, multi-echo gradient echo (MGRE) sequence used for myocardial T2* quantification is very sensitive to respiratory motion and may not be feasible in patients who are unable to breath-hold. We propose a free-breathing myocardial T2* mapping approach that combines a single-shot gradient-echo echo-planar imaging (GRE-EPI) sequence for T2*-weighted image acquisition with automatic non-rigid motion correction (MOCO) of respiratory motion between single-shot images.MethodsECG-triggered T2*-weighted images at different echo times were acquired by a black-blood, single-shot GRE-EPI sequence during free-breathing. A single image at a single TE is acquired in each heartbeat. Automatic non-rigid MOCO was applied to correct for in-plane respiratory motion before pixel-wise T2* mapping. In a total of 117 patients referred for clinical cardiac magnetic resonance exams, the free-breathing MOCO GRE-EPI sequence was compared to the breath-hold segmented MGRE approach. Image quality was scored independently by 2 experienced observers blinded to the particular image acquisition strategy. T2* measurements in the interventricular septum and in the liver were compared for the two methods in all cases with adequate image quality.ResultsT2* maps were acquired in all 117 patients using the breath-hold MGRE and the free-breathing MOCO GRE-EPI approaches, including 8 patients with myocardial iron overload and 25 patients with hepatic iron overload. The mean image quality of the free-breathing MOCO GRE-EPI images was scored significantly higher than that of the breath-hold MGRE images by both reviewers. Out of the 117 studies, 21 breath-hold MGRE studies (17.9xa0% of all the patients) were scored to be less than adequate or very poor by both reviewers, while only 2 free-breathing MOCO GRE-EPI studies were scored to be less than adequate image quality. In a comparative evaluation of the images with at least adequate quality, the intra-class correlation coefficients for myocardial and liver T2* were 0.868 and 0.986 respectively (pu2009<u20090.001), indicating that the T2* measured by breath-hold MGRE and free-breathing MOCO GRE-EPI were in close agreement. The coefficient of variation between the breath-hold and free-breathing approaches for myocardial and liver T2* were 9.88xa0% and 9.38xa0% respectively. Bland-Altman plots demonstrated good absolute agreement of T2* in the interventricular septum and the liver from the free-breathing and breath-hold approaches (mean differences -0.03 and 0.16xa0ms, respectively).ConclusionThe free-breathing approach described for T2* mapping using MOCO GRE-EPI enables accurate myocardial and liver T2* measurements and is insensitive to respiratory motion.

Venous oxygen saturation estimation from multiple T2 maps with varying inter-echo spacing

Background Dependence of blood T2 on O2 saturation has led to noninvasive MRI-based techniques for determining venous O2 saturation (SvO2) [1-3]. However, applying a general calibration factor derived from in vitro experiments can lead to inaccurate and largely varying SvO2 estimates in the target population. We aim to show that based on the Luz-Meiboom relation 1/T2 = 1/T2o + Hct(1-Hct) τex [(1-%SO2/100)aω0] (1-2*τex/τ180 tanh(τ180/2*τex))[4], individual SvO2 can be determined from multiple T2 maps, each acquired at a specific inter-echo spacing (τ180).

MR elastography as a method to estimate aortic stiffness and its comparison against MR based pulse wave velocity measurement.

Background Arterial (aortic) stiffness is a well-recognized pathophysiological change that plays a significant role in the determination of risk factors for various cardiovascular diseases [1]. Measurement of arterial stiffness using pulse wave velocity (PWV) is the gold standard among non-invasive modalities. Recently, a novel non-invasive MRI based technique known as magnetic resonance elastography (MRE) was developed to determine the stiffness of the aorta[2]. The aim of the study is to compare the abdominal aortic stiffness obtained using MRI based PWV stiffness measurements against MRE based stiffness measurements.

CMR-based blood oximetry via multi-parametric estimation using multiple T2 measurements

BackgroundMeasurement of blood oxygen saturation (O2 saturation) is of great importance for evaluation of patients with many cardiovascular diseases, but currently there are no established non-invasive methods to measure blood O2 saturation in the heart. While T2-based CMR oximetry methods have been previously described, these approaches rely on technique-specific calibration factors that may not generalize across patient populations and are impractical to obtain in individual patients. We present a solution that utilizes multiple T2 measurements made using different inter-echo pulse spacings. These data are jointly processed to estimate all unknown parameters, including O2 saturation, in the Luz-Meiboom (L-M) model. We evaluated the accuracy of the proposed method against invasive catheterization in a porcine hypoxemia model.MethodsSufficient data diversity to estimate the various unknown parameters of the L-M model, including O2 saturation, was achieved by acquiring four T2 maps, each at a different τ180 (12, 15, 20, and 25xa0ms). Venous and arterial blood T2 values from these maps, together with hematocrit and arterial O2 saturation, were jointly processed to derive estimates for venous O2 saturation and other nuisance parameters in the L-M model. The technique was validated by a progressive graded hypoxemia experiment in seven pigs. CMR estimates of O2 saturation in the right ventricle were compared against a reference O2 saturation obtained by invasive catheterization from the right atrium in each pig, at each hypoxemia stage. O2 saturation derived from the proposed technique was also compared against the previously described method of applying a global calibration factor (K) to the simplified L-M model.ResultsVenous O2 saturation results obtained using the proposed CMR oximetry method exhibited better agreement (yxa0=xa00.84×xa0+xa012.29, R2xa0=xa00.89) with invasive blood gas analysis when compared to O2 saturation estimated by a global calibration method (yxa0=xa00.69×xa0+xa027.52, R2xa0=xa00.73).ConclusionsWe have demonstrated a novel, non-invasive method to estimate O2 saturation using quantitative T2 mapping. This technique may provide a valuable addition to the diagnostic utility of CMR in patients with congenital heart disease, heart failure, and pulmonary hypertension.

An improved preparation pulse for quantitative t2 mapping of blood in the cardiac chambers

Background T2 is sensitive to hemoglobin oxygen saturation (%HbO2). Non-invasive, rapid in-vivo quantification of %HbO2 based on the T2 of blood may be useful in patients with congenital heart disease. Although singleshot, T2-prepared SSFP enables rapid myocardial T2 quantification [1], flow sensitivity of the T2 preparation, especially at later echo times, may cause an underestimation of T2 values in flowing blood. We aim to reduce flow sensitivity of the T2 preparation pulse for rapid and accurate quantification of T2 in blood.