A systematic comparison of cardiovascular magnetic resonance and high resolution histological fibrosis quantification in a chronic porcine infarct model.

The noninvasive reference standard for myocardial fibrosis detection on cardiovascular magnetic resonance imaging (CMR) is late gadolinium enhancement (LGE). Currently there is no consensus on the preferred method for LGE quantification. Moreover myocardial wall thickening (WT) and strain are measures of regional deformation and function. The aim of this research was to systematically compare in vivo CMR parameters, such as LGE, WT and strain, with histological fibrosis quantification. Eight weeks after 90 min ischemia/reperfusion of the LAD artery, 16 pigs underwent in vivo Cine and LGE CMR. Histological sections from transverse heart slices were digitally analysed for fibrosis quantification. Mean fibrosis percentage of analysed sections was related to the different CMR techniques (using segmentation or feature tracking software) for each slice using a linear mixed model analysis. The full width at half maximum (FWHM) technique for quantification of LGE yielded the highest R2 of 60%. Cine derived myocardial WT explained 16-36% of the histological myocardial fibrosis. The peak circumferential and radial strain measured by feature tracking could explain 15 and 10% of the variance of myocardial fibrosis, respectively. The used method to systematically compare CMR image data with digital histological images is novel and feasible. Myocardial WT and strain were only modestly related with the amount of fibrosis. The fully automatic FWHM analysis technique is the preferred method to detect myocardial fibrosis.

Endogenous assessment of diffuse myocardial fibrosis in patients with T1ρ -mapping.

PURPOSE: Recently, it was shown that a significantly higher T1ρ is found in compact myocardial fibrosis after chronic myocardial infarction. In this study, we investigated the feasibility of native T1ρ -mapping for the detection of diffuse myocardial fibrosis in patients with dilated cardiomyopathy (DCM). MATERIALS AND METHODS: T1ρ -mapping was performed on three explanted hearts from DCM patients at 3 Tesla (T). Histological fibrosis quantification was performed, and compared with the T1ρ -relaxation times in the heart. Furthermore, twenty DCM patients underwent an MRI at 1.5T. Native T1ρ -maps, native T1 -maps, and extracellular volume (ECV)-maps were acquired. Additionally, eight healthy volunteers were scanned for reference values. RESULTS: A significant correlation (Pearson r = 0.49; P = 0.005) was found between ex vivo T1ρ -values and fibrosis fraction from histology. Additionally, a significantly higher T1ρ -relaxation time (55.2 ± 2.7 ms) was found in DCM patients compared with healthy control subjects (51.5 ± 1.2 ms) (P = 0.0024). The relation between in vivo T1ρ -values and ECV-values was significant (Pearson r = 0.66). No significant relation was found between native T1 - and ECV-values in this study (P = 0.89). CONCLUSION: This study showed proof of principle for the endogenous detection of diffuse myocardial fibrosis with T1ρ -MRI. Ex vivo and in vivo experiments showed promising results that T1ρ -MRI can be used to measure the extent of diffuse myocardial fibrosis in the myocardium. LEVEL OF EVIDENCE: 2 J. Magn. Reson. Imaging 2017;45:132-138.

Single Breath-Hold T1ρ-Mapping of the Heart for Endogenous Assessment of Myocardial Fibrosis.

OBJECTIVES: In this study, we propose a method to acquire high spatial-resolution T1ρ-maps, which allows bright and black-blood imaging, in a single breath-hold. To validate this innovative method, the reproducibility was tested in phantoms and volunteers. Lastly, the sensitivity and specificity for infarct detection was compared with the criterion standard late gadolinium enhancement (LGE). METHODS: T1ρ-mapping was performed using a T1ρ-prepared balanced steady-state free precession sequence at 1.5 T and 3 T. Five images with increasing spin-lock preparation times (spin-lock = 0, 10, 20, 30, 40 milliseconds, amplitude = 500 Hz) were acquired with an interval of 3 beats. Black-blood imaging was performed using a double inversion pulse sequence. The method was tested in 2 times 10 healthy volunteers at 1.5 and 3 T and in 9 myocardial infarction patients at 1.5 T. T1ρ-maps, and LGE images were scored for presence and extent of myocardial scarring. RESULTS: Phantom results show that the proposed T1ρ-mapping method gives accurate T1ρ-values. The mean T1ρ-relaxation time of the myocardium in healthy controls was 52.8 ± 1.8 milliseconds at 1.5 T and 46.4 ± 1.8 milliseconds at 3 T. In patients, the T1ρ of infarcted myocardium was (82.4 ± 5.2 milliseconds), and the T1ρ of remote myocardium was (54.2 ± 2.8 milliseconds; P < 0.0001). Sensitivity of infarct detection on a T1ρ-map was 70%, with a specificity of 94%, compared with LGE. CONCLUSIONS: In this study, we have investigated a method to acquire high spatial-resolution T1ρ-maps of the heart in a single breath-hold. This method proved to be reproducible and had high specificity compared with LGE and can thus be used for the endogenous detection of myocardial fibrosis in patients with ischemic cardiomyopathy.

Xenotransplantation of Human Cardiomyocyte Progenitor Cells Does Not Improve Cardiac Function in a Porcine Model of Chronic Ischemic Heart Failure. Results from a Randomized, Blinded, Placebo Controlled Trial.

BACKGROUND: Recently cardiomyocyte progenitor cells (CMPCs) were successfully isolated from fetal and adult human hearts. Direct intramyocardial injection of human CMPCs (hCMPCs) in experimental mouse models of acute myocardial infarction significantly improved cardiac function compared to controls. AIM: Here, our aim was to investigate whether xenotransplantation via intracoronary infusion of fetal hCMPCs in a pig model of chronic myocardial infarction is safe and efficacious, in view of translation purposes. METHODS & RESULTS: We performed a randomized, blinded, placebo controlled trial. Four weeks after ischemia/reperfusion injury by 90 minutes of percutaneous left anterior descending artery occlusion, pigs (n = 16, 68.5 ± 5.4 kg) received intracoronary infusion of 10 million fetal hCMPCs or placebo. All animals were immunosuppressed by cyclosporin (CsA). Four weeks after infusion, endpoint analysis by MRI displayed no difference in left ventricular ejection fraction, left ventricular end diastolic and left ventricular end systolic volumes between both groups. Serial pressure volume (PV-)loop and echocardiography showed no differences in functional parameters between groups at any timepoint. Infarct size at follow-up, measured by late gadolinium enhancement MRI showed no difference between groups. Intracoronary pressure and flow measurements showed no signs of coronary obstruction 30 minutes after cell infusion. No premature death occurred in cell treated animals. CONCLUSION: Xenotransplantation via intracoronary infusion of hCMPCs is feasible and safe, but not associated with improved left ventricular performance and infarct size compared to placebo in a porcine model of chronic myocardial infarction.

Muscle Metabolic Responses During Dynamic In-Magnet Exercise Testing: A Pilot Study in Children with an Idiopathic Inflammatory Myopathy.

RATIONALE AND OBJECTIVES: The clinical utility of supine in-magnet bicycling in combination with phosphorus magnetic resonance spectroscopy ((31)P MRS) to evaluate quadriceps muscle metabolism was examined in four children with juvenile dermatomyositis (JDM) in remission and healthy age- and gender-matched controls. MATERIALS AND METHODS: Two identical maximal supine bicycling tests were performed using a magnetic resonance-compatible ergometer. During the first test, cardiopulmonary performance was established in the exercise laboratory. During the second test, quadriceps energy balance and acid/base balance during incremental exercise and phosphocreatine recovery were determined using (31)P MRS. RESULTS: During the first test, no significant differences were found between patients with JDM and their healthy peers regarding cardiopulmonary performance. The outcomes of the first test indicate that both groups attained maximal performance. During the second test, quadriceps phosphocreatine and pH time courses were similar in all but one patient experiencing idiopathic postexercise pain. This patient demonstrated faster phosphocreatine depletion and acidification during exercise, yet postexercise mitochondrial adenosine triphosphate synthesis rate measured by phosphocreatine recovery kinetics was approximately twofold faster than control (time constant 23 seconds vs 43 ± 7 seconds, respectively). CONCLUSIONS: These results highlight the utility of in-magnet cycle ergometry in combination with (31)P MRS to assess and monitor muscle energetic patterns in pediatric patients with inflammatory myopathies.

Advances in cardiac magnetic resonance imaging of congenital heart disease.

Due to advances in cardiac surgery, survival of patients with congenital heart disease has increased considerably during the past decades. Many of these patients require repeated cardiovascular magnetic resonance imaging to assess cardiac anatomy and function. In the past decade, technological advances have enabled faster and more robust cardiovascular magnetic resonance with improved image quality and spatial as well as temporal resolution. This review aims to provide an overview of advances in cardiovascular magnetic resonance hardware and acquisition techniques relevant to both pediatric and adult patients with congenital heart disease and discusses the techniques used to assess function, anatomy, flow and tissue characterization.

Endogenous contrast MRI of cardiac fibrosis: beyond late gadolinium enhancement.

The aim of this review is to provide an overview of detection of cardiac fibrosis with MRI using current standards and novel endogenous MRI techniques. Assessment of cardiac fibrosis is important for diagnosis, prediction of prognosis and follow-up after therapy. During the past years, progress has been made in fibrosis detection using MRI. Cardiac infarct size can be assessed noninvasively with late gadolinium enhancement. Several methods for fibrosis detection using endogenous contrast have been developed, such as native T1 -mapping, T1ρ -mapping, Magnetization transfer imaging, and T2 *-mapping. Each of these methods will be described, providing the basic methodology, showing potential applications from applied studies, and discussing the potential and challenges or pitfalls. We will also identify future steps and developments that are needed for bringing these methods to the clinical practice.

Endogenous assessment of chronic myocardial infarction with T(1ρ)-mapping in patients.

BACKGROUND: Detection of cardiac fibrosis based on endogenous magnetic resonance (MR) characteristics of the myocardium would yield a measurement that can provide quantitative information, is independent of contrast agent concentration, renal function and timing. In ex vivo myocardial infarction (MI) tissue, it has been shown that a significantly higher T(1ρ) is found in the MI region, and studies in animal models of chronic MI showed the first in vivo evidence for the ability to detect myocardial fibrosis with native T(1ρ)-mapping. In this study we aimed to translate and validate T(1ρ)-mapping for endogenous detection of chronic MI in patients. METHODS: We first performed a study in a porcine animal model of chronic MI to validate the implementation of T(1ρ)-mapping on a clinical cardiovascular MR scanner and studied the correlation with histology. Subsequently a clinical protocol was developed, to assess the feasibility of scar tissue detection with native T(1ρ)-mapping in patients (n = 21) with chronic MI, and correlated with gold standard late gadolinium enhancement (LGE) CMR. Four T1ρ-weighted images were acquired using a spin-lock preparation pulse with varying duration (0, 13, 27, 45 ms) and an amplitude of 750 Hz, and a T(1ρ)-map was calculated. The resulting T(1ρ)-maps and LGE images were scored qualitatively for the presence and extent of myocardial scarring using the 17-segment AHA model. RESULTS: In the animal model (n = 9) a significantly higher T(1ρ) relaxation time was found in the infarct region (61 ± 11 ms), compared to healthy remote myocardium (36 ± 4 ms) . In patients a higher T(1ρ) relaxation time (79 ± 11 ms) was found in the infarct region than in remote myocardium (54 ± 6 ms). Overlap in the scoring of scar tissue on LGE images and T(1ρ)-maps was 74%. CONCLUSION: We have shown the feasibility of native T(1ρ)-mapping for detection of infarct area in patients with a chronic myocardial infarction. In the near future, improvements on the T(1ρ)-mapping sequence could provide a higher sensitivity and specificity. This endogenous method could be an alternative for LGE imaging, and provide additional quantitative information on myocardial tissue characteristics.

31P MR spectroscopy and computational modeling identify a direct relation between Pi content of an alkaline compartment in resting muscle and phosphocreatine resynthesis kinetics in active muscle in humans.

The assessment of mitochondrial properties in skeletal muscle is important in clinical research, for instance in the study of diabetes. The gold standard to measure mitochondrial capacity non-invasively is the phosphocreatine (PCr) recovery rate after exercise, measured by (31)P Magnetic Resonance spectroscopy ((31)P MRS). Here, we sought to expand the evidence base for an alternative method to assess mitochondrial properties which uses (31)P MRS measurement of the Pi content of an alkaline compartment attributed to mitochondria (Pi2; as opposed to cytosolic Pi (Pi1)) in resting muscle at high magnetic field. Specifically, the PCr recovery rate in human quadriceps muscle was compared with the signal intensity of the Pi2 peak in subjects with varying mitochondrial content of the quadriceps muscle as a result of athletic training, and the results were entered into a mechanistic computational model of mitochondrial metabolism in muscle to test if the empirical relation between Pi2/Pi1 ratio and the PCr recovery was consistent with theory. Localized (31)P spectra were obtained at 7T from resting vastus lateralis muscle to measure the intensity of the Pi2 peak. In the endurance trained athletes a Pi2/Pi1 ratio of 0.07 ± 0.01 was found, compared to a significantly lower (p<0.05) Pi2/Pi1 ratio of 0.03 ± 0.01 in the normally active group. Next, PCr recovery kinetics after in magnet bicycle exercise were measured at 1.5T. For the endurance trained athletes, a time constant τPCr 12 ± 3 s was found, compared to 24 ± 5s in normally active subjects. Without any parameter optimization the computational model prediction matched the experimental data well (r(2) of 0.75). Taken together, these results suggest that the Pi2 resonance in resting human skeletal muscle observed at 7T provides a quantitative MR-based functional measure of mitochondrial density.

Prediction of muscle energy states at low metabolic rates requires feedback control of mitochondrial respiratory chain activity by inorganic phosphate.

The regulation of the 100-fold dynamic range of mitochondrial ATP synthesis flux in skeletal muscle was investigated. Hypotheses of key control mechanisms were included in a biophysical model of oxidative phosphorylation and tested against metabolite dynamics recorded by (31)P nuclear magnetic resonance spectroscopy ((31)P MRS). Simulations of the initial model featuring only ADP and Pi feedback control of flux failed in reproducing the experimentally sampled relation between myoplasmic free energy of ATP hydrolysis (ΔG(p) = ΔG(p)(o')+RT ln ([ADP][Pi]/[ATP]) and the rate of mitochondrial ATP synthesis at low fluxes (<0.2 mM/s). Model analyses including Monte Carlo simulation approaches and metabolic control analysis (MCA) showed that this problem could not be amended by model re-parameterization, but instead required reformulation of ADP and Pi feedback control or introduction of additional control mechanisms (feed forward activation), specifically at respiratory Complex III. Both hypotheses were implemented and tested against time course data of phosphocreatine (PCr), Pi and ATP dynamics during post-exercise recovery and validation data obtained by (31)P MRS of sedentary subjects and track athletes. The results rejected the hypothesis of regulation by feed forward activation. Instead, it was concluded that feedback control of respiratory chain complexes by inorganic phosphate is essential to explain the regulation of mitochondrial ATP synthesis flux in skeletal muscle throughout its full dynamic range.