Development and Application of Gadolinium Free Cardiac Magnetic Resonance Fibrosis Imaging for Multiscale Study of Heart Failure in Patients with End Stage Renal Disease

Cardiac magnetic resonance (CMR) is a powerful tool to noninvasively image ventricular fibrosis. Late gadolinium enhancement (LGE) CMR identifies focal and, with T1 mapping, diffuse fibrosis. Despite prevalent cardiac fibrosis and heart failure, patients with end stage renal disease (ESRD) are excluded from LGE. Absence of a suitable diagnostic has limited the understanding of heart failure and obstructed development of therapies in the setting of ESRD. A quantitative, gadolinium free fibrosis detection method could overcome this critical barrier, propelling the advancement of diagnostic, monitoring, and therapy options. This project describes the development of a gadolinium free CMR technique and application for cardiac fibrosis measurement in patients with ESRD. Magnetization transfer (MT) occurs during standard cine balanced steady state free precession (bSSFP) CMR, where extracellular matrix protons exchange magnetization with water molecules. Extracellular water volume expansion, concomitant with fibrosis, reduces MT and subtly elevates signal intensity. Our technique, 2-pt bSSFP, extracts endogenous contrast sensitive to tissue fibrosis by obtaining pairs of high and low MT-weighted images and calculating normalized signal differences, denoted by ΔS/So. We tested 2-pt bSSFP in patients referred for CMR and found excellent agreement spatially with LGE and quantitatively with extracellular volume fraction. Diagnostic and clinical application of 2-pt bSSFP was comparable to LGE. We applied 2-pt bSSFP to patients with ESRD for multiscale comparison with correlates of fibrosis ranging from blood biomarkers to whole organ function. Patients with ESRD displayed hypertrophy with reduced contraction, but elevated ΔS/So and fibrosis. Some biomarkers correlated with both hypertrophy and fibrosis, highlighting the need to distinguish between hypertrophic and fibrotic remodeling. We monitored fibrosis over 1 year using 2-pt bSSFP in a cohort of patients with ESRD. ΔS/So and fibrotic burden increased substantially, despite minor changes in structure and function. Collectively these studies validate and apply 2-pt bSSFP for gadolinium free fibrosis CMR in patients with ESRD. While ventricular structure and function are commensurate with progression toward heart failure, it is now possible to specifically describe global and focal patterns of cardiac fibrosis in ESRD, along with comparisons to blood biomarkers which may lead to improved diagnostics and molecular treatment targets

Influence of Longitudinal Position on the Evolution of Steady-State Signal in Cardiac Cine Balanced Steady-State Free Precession Imaging

Background: Emerging quantitative cardiac magnetic resonance imaging (CMRI) techniques use cine balanced steady-state free precession (bSSFP) to measure myocardial signal intensity and probe underlying physiological parameters. This correlation assumes that steady-state is maintained uniformly throughout the heart in space and time. Purpose: To determine the effects of longitudinal cardiac motion and initial slice position on signal deviation in cine bSSFP imaging by comparing two-dimensional (2D) and three-dimensional (3D) acquisitions. Material and Methods: Nine healthy volunteers completed cardiac MRI on a 1.5-T scanner. Short axis images were taken at six slice locations using both 2D and 3D cine bSSFP. 3D acquisitions spanned two slices above and below selected slice locations. Changes in myocardial signal intensity were measured across the cardiac cycle and compared to longitudinal shortening. Results: For 2D cine bSSFP, 46% ± 9% of all frames and 84% ± 13% of end-diastolic frames remained within 10% of initial signal intensity. For 3D cine bSSFP the proportions increased to 87% ± 8% and 97% ± 5%. There was no correlation between longitudinal shortening and peak changes in myocardial signal. The initial slice position significantly impacted peak changes in signal intensity for 2D sequences (P \u3c 0.001). Conclusion: The initial longitudinal slice location significantly impacts the magnitude of deviation from steady-state in 2D cine bSSFP that is only restored at the center of a 3D excitation volume. During diastole, a transient steady-state is established similar to that achieved with 3D cine bSSFP regardless of slice location

Gadolinium Free Cardiovascular Magnetic Resonance with 2-Point Cine Balanced Steady State Free Precession

BACKGROUND: Cardiovascular magnetic resonance (CMR) of ventricular structure and function is widely performed using cine balanced steady state free precession (bSSFP) MRI. The bSSFP signal of myocardium is weighted by magnetization transfer (MT) and T1/T2-relaxation times. In edematous and fibrotic tissues, increased T2 and reduced MT lead to increased signal intensity on images acquired with high excitation flip angles. We hypothesized that acquisition of two differentially MT-weighted bSSFP images (termed 2-point bSSFP) can identify tissue that would enhance with gadolinium similar to standard of care late gadolinium enhancement (LGE). METHODS: Cine bSSFP images (flip angles of 5° and 45°) and native-T1 and T2 maps were acquired in one mid-ventricular slice in 47 patients referred for CMR and 10 healthy controls. Afterwards, LGE images and post-contrast T1 maps were acquired and gadolinium partition coefficient (GPC) was calculated. Maps of ΔS/So were calculated as (S45-S5)/S5*100 (%), where Sflip_angle is the voxel signal intensity. RESULTS: Twenty three patients demonstrated areas of myocardial hyper-enhancement with LGE. In enhanced regions, ΔS/So, native-T1, T2, and GPC were heightened (p \u3c 0.05 vs. non-enhanced tissues). ΔS/So, native-T1, and T2 all demonstrated association with GPC, however the association was strongest for ΔS/So. Bland-Altman analysis revealed a slight bias towards larger volume of enhancement with ΔS/So compared to LGE, and similar transmurality. Subjective analysis with 2-blinded expert readers revealed agreement between ΔS/So and LGE of 73.4 %, with false positive detection of 16.7 % and false negative detection of 15.2 %. CONCLUSIONS: Gadolinium free 2-point bSSFP identified tissue that enhances at LGE with strong association to GPC. Our results suggest that with further development, MT-weighted CMR could be used similar to LGE for diagnostic imaging

Quantitative Gadolinium-Free Cardiac Fibrosis Imaging in End Stage Renal Disease Patients Reveals a Longitudinal Correlation with Structural and Functional Decline

Patients with end stage renal disease (ESRD) suffer high mortality from arrhythmias linked to fibrosis, but are contraindicated to late gadolinium enhancement magnetic resonance imaging (MRI). We present a quantitative method for gadolinium-free cardiac fibrosis imaging using magnetization transfer (MT) weighted MRI, and probe correlations with widely used surrogate markers including cardiac structure and contractile function in patients with ESRD. In a sub-group of patients who returned for follow-up imaging after one year, we examine the correlation between changes in fibrosis and ventricular structure/function. Quantification of changes in MT revealed significantly greater fibrotic burden in patients with ESRD compared to a healthy age matched control cohort. Ventricular mechanics, including circumferential strain and diastolic strain rate were unchanged in patients with ESRD. No correlation was observed between fibrotic burden and concomitant measures of either circumferential or longitudinal strains or strain rates. However, among patients who returned for follow up examination a strong correlation existed between initial fibrotic burden and subsequent loss of contractile function. Gadolinium-free myocardial fibrosis imaging in patients with ESRD revealed a complex and longitudinal, not contemporary, association between fibrosis and ventricular contractile function

Gadolinium free cardiovascular magnetic resonance with 2-point Cine balanced steady state free precession

BACKGROUND: Cardiovascular magnetic resonance (CMR) of ventricular structure and function is widely performed using cine balanced steady state free precession (bSSFP) MRI. The bSSFP signal of myocardium is weighted by magnetization transfer (MT) and T1/T2-relaxation times. In edematous and fibrotic tissues, increased T2 and reduced MT lead to increased signal intensity on images acquired with high excitation flip angles. We hypothesized that acquisition of two differentially MT-weighted bSSFP images (termed 2-point bSSFP) can identify tissue that would enhance with gadolinium similar to standard of care late gadolinium enhancement (LGE). METHODS: Cine bSSFP images (flip angles of 5° and 45°) and native-T1 and T2 maps were acquired in one mid-ventricular slice in 47 patients referred for CMR and 10 healthy controls. Afterwards, LGE images and post-contrast T1 maps were acquired and gadolinium partition coefficient (GPC) was calculated. Maps of ΔS/S(o) were calculated as (S(45)-S(5))/S(5)*100 (%), where S(flip_angle) is the voxel signal intensity. RESULTS: Twenty three patients demonstrated areas of myocardial hyper-enhancement with LGE. In enhanced regions, ΔS/S(o), native-T1, T2, and GPC were heightened (p < 0.05 vs. non-enhanced tissues). ΔS/S(o), native-T1, and T2 all demonstrated association with GPC, however the association was strongest for ΔS/S(o). Bland-Altman analysis revealed a slight bias towards larger volume of enhancement with ΔS/S(o) compared to LGE, and similar transmurality. Subjective analysis with 2-blinded expert readers revealed agreement between ΔS/S(o) and LGE of 73.4 %, with false positive detection of 16.7 % and false negative detection of 15.2 %. CONCLUSIONS: Gadolinium free 2-point bSSFP identified tissue that enhances at LGE with strong association to GPC. Our results suggest that with further development, MT-weighted CMR could be used similar to LGE for diagnostic imaging. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12968-015-0194-1) contains supplementary material, which is available to authorized users

Myocardial native-T1 times are elevated as a function of hypertrophy, HbA1c, and heart rate in diabetic adults without diffuse fibrosis

PurposeCardiac native-T1 times have correlated to extracellular volume fraction in patients with confirmed fibrosis. However, whether other factors that can occur either alongside or independently of fibrosis including increased intracellular water volume, altered magnetization transfer (MT), or glycation of hemoglobin, lengthen T1 times in the absence of fibrosis remains unclear. The current study examined whether native-T1 times are elevated in hypertrophic diabetics with elevated hemoglobin A1C (HbA1c) without diffuse fibrosis.MethodsNative-T1 times were quantified in 27 diabetic and 10 healthy adults using a modified Look-Locker imaging (MOLLI) sequence at 1.5 T. The MT ratio (MTR) was quantified using dual flip angle cine balanced steady-state free precession. Gadolinium (0.2 mmol/kg Gd-DTPA) was administered as a bolus and post-contrast T1-times were quantified after 15 min. Means were compared using a two-tailed student's t-test, while correlations were assessed using Pearson's correlations.ResultsWhile left ventricular volumes, ejection fraction, and cardiac output were similar between groups, left ventricular mass and mass-to-volume ratio (MVR) were significantly higher in diabetic adults. Mean ECV (0.25 ± 0.02 Healthy vs. 0.25 ± 0.03 Diabetic, P = 0.47) and MTR (125 ± 16% Healthy vs. 125 ± 9% Diabetic, P = 0.97) were similar, however native-T1 times were significantly higher in diabetics (1016 ± 21 ms Healthy vs. 1056 ± 31 ms Diabetic, P = 0.00051). Global native-T1 times correlated with MVR (ρ = 0.43, P = 0.008) and plasma HbA1c levels (ρ = 0.43, P = 0.0088) but not ECV (ρ = 0.06, P = 0.73). Septal native-T1 times correlated with septal wall thickness (ρ = 0.50, P = 0.001).ConclusionIn diabetic adults with normal ECV values, elevated native-T1 times may reflect increased intracellular water volume and changes secondary to increased hemoglobin glycation