Prolonged ß-adrenergic stimulation disperses ryanodine receptor clusters in cardiomyocytes and has implications for heart failure.

Ryanodine receptors (RyRs) exhibit dynamic arrangements in cardiomyocytes, and we previously showed that 'dispersion' of RyR clusters disrupts Ca2+ homeostasis during heart failure (HF) (Kolstad et al., eLife, 2018). Here, we investigated whether prolonged ß-adrenergic stimulation, a hallmark of HF, promotes RyR cluster dispersion and examined the underlying mechanisms. We observed that treatment of healthy rat cardiomyocytes with isoproterenol for 1 hr triggered progressive fragmentation of RyR clusters. Pharmacological inhibition of Ca2+/calmodulin-dependent protein kinase II (CaMKII) reversed these effects, while cluster dispersion was reproduced by specific activation of CaMKII, and in mice with constitutively active Ser2814-RyR. A similar role of protein kinase A (PKA) in promoting RyR cluster fragmentation was established by employing PKA activation or inhibition. Progressive cluster dispersion was linked to declining Ca2+ spark fidelity and magnitude, and slowed release kinetics from Ca2+ propagation between more numerous RyR clusters. In healthy cells, this served to dampen the stimulatory actions of ß-adrenergic stimulation over the longer term and protect against pro-arrhythmic Ca2+ waves. However, during HF, RyR dispersion was linked to impaired Ca2+ release. Thus, RyR localization and function are intimately linked via channel phosphorylation by both CaMKII and PKA, which, while finely tuned in healthy cardiomyocytes, underlies impaired cardiac function during pathology.

Extreme altitude induces divergent mass reduction of right and left ventricle in mountain climbers.

Mountain climbing at high altitude implies exposure to low levels of oxygen, low temperature, wind, physical and psychological stress, and nutritional insufficiencies. We examined whether right ventricular (RV) and left ventricular (LV) myocardial masses were reversibly altered by exposure to extreme altitude. Magnetic resonance imaging and echocardiography of the heart, dual x-ray absorptiometry scan of body composition, and blood samples were obtained from ten mountain climbers before departure to Mount Everest or Dhaulagiri (baseline), 13.5 ± 1.5 days after peaking the mountain (post-hypoxia), and six weeks and six months after expeditions exceeding 8000 meters above sea level. RV mass was unaltered after extreme altitude, in contrast to a reduction in LV mass by 11.8 ± 3.4 g post-hypoxia (p = 0.001). The reduction in LV mass correlated with a reduction in skeletal muscle mass. After six weeks, LV myocardial mass was restored to baseline values. Extreme altitude induced a reduction in LV end-diastolic volume (20.8 ± 7.7 ml, p = 0.011) and reduced E', indicating diastolic dysfunction, which were restored after six weeks follow-up. Elevated circulating interleukin-18 after extreme altitude compared to follow-up levels, might have contributed to reduced muscle mass and diastolic dysfunction. In conclusion, the mass of the RV, possibly exposed to elevated afterload, was not changed after extreme altitude, whereas LV mass was reduced. The reduction in LV mass correlated with reduced skeletal muscle mass, indicating a common denominator, and elevated circulating interleukin-18 might be a mechanism for reduced muscle mass after extreme altitude.

A 4D continuous representation of myocardial velocity fields from tissue phase mapping magnetic resonance imaging.

Myocardial velocities carry important diagnostic information in a range of cardiac diseases, and play an important role in diagnosing and grading left ventricular diastolic dysfunction. Tissue Phase Mapping (TPM) Magnetic Resonance Imaging (MRI) enables discrete sampling of the myocardium's underlying smooth and continuous velocity field. This paper presents a post-processing framework for constructing a spatially and temporally smooth and continuous representation of the myocardium's velocity field from TPM data. In the proposed scheme, the velocity field is represented through either linear or cubic B-spline basis functions. The framework facilitates both interpolation and noise reducing approximation. As a proof-of-concept, the framework was evaluated using artificially noisy (i.e., synthetic) velocity fields created by adding different levels of noise to an original TPM data. The framework's ability to restore the original velocity field was investigated using Bland-Altman statistics. Moreover, we calculated myocardial material point trajectories through temporal integration of the original and synthetic fields. The effect of noise reduction on the calculated trajectories was investigated by assessing the distance between the start and end position of material points after one complete cardiac cycle (end point error). We found that the Bland-Altman limits of agreement between the original and the synthetic velocity fields were reduced after application of the framework. Furthermore, the integrated trajectories exhibited consistently lower end point error. These results suggest that the proposed method generates a realistic continuous representation of myocardial velocity fields from noisy and discrete TPM data. Linear B-splines resulted in narrower limits of agreement between the original and synthetic fields, compared to Cubic B-splines. The end point errors were also consistently lower for Linear B-splines than for cubic. Linear B-splines therefore appear to be more suitable for TPM data.

Etiology-Dependent Impairment of Diastolic Cardiomyocyte Calcium Homeostasis in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Whereas heart failure with reduced ejection fraction (HFrEF) is associated with ventricular dilation and markedly reduced systolic function, heart failure with preserved ejection fraction (HFpEF) patients exhibit concentric hypertrophy and diastolic dysfunction. Impaired cardiomyocyte Ca2+ homeostasis in HFrEF has been linked to disruption of membrane invaginations called t-tubules, but it is unknown if such changes occur in HFpEF. OBJECTIVES: This study examined whether distinct cardiomyocyte phenotypes underlie the heart failure entities of HFrEF and HFpEF. METHODS: T-tubule structure was investigated in left ventricular biopsies obtained from HFrEF and HFpEF patients, whereas cardiomyocyte Ca2+ homeostasis was studied in rat models of these conditions. RESULTS: HFpEF patients exhibited increased t-tubule density in comparison with control subjects. Super-resolution imaging revealed that higher t-tubule density resulted from both tubule dilation and proliferation. In contrast, t-tubule density was reduced in patients with HFrEF. Augmented collagen deposition within t-tubules was observed in HFrEF but not HFpEF hearts. A causative link between mechanical stress and t-tubule disruption was supported by markedly elevated ventricular wall stress in HFrEF patients. In HFrEF rats, t-tubule loss was linked to impaired systolic Ca2+ homeostasis, although diastolic Ca2+ removal was also reduced. In contrast, Ca2+ transient magnitude and release kinetics were largely maintained in HFpEF rats. However, diastolic Ca2+ impairments, including reduced sarco/endoplasmic reticulum Ca2+-ATPase activity, were specifically observed in diabetic HFpEF but not in ischemic or hypertensive models. CONCLUSIONS: Although t-tubule disruption and impaired cardiomyocyte Ca2+ release are hallmarks of HFrEF, such changes are not prominent in HFpEF. Impaired diastolic Ca2+ homeostasis occurs in both conditions, but in HFpEF, this mechanism for diastolic dysfunction is etiology-dependent.

Analysis of right ventricular mass from magnetic resonance imaging data: a simple post-processing algorithm for correction of partial-volume effects.

Magnetic resonance imaging (MRI) of the right ventricle (RV) offers important diagnostic information, but the accuracy of this information is hampered by the complex geometry of the RV. Here, we propose a novel postprocessing algorithm that corrects for partial-volume effects in the analysis of standard MRI cine images of RV mass (RVm) and evaluate the method in clinical and preclinical data. Self-corrected RVm measurement was compared with conventionally measured RVm in 16 patients who showed different clinical indications for cardiac MRI and in 17 Wistar rats with different degrees of pulmonary congestion. The rats were studied under isoflurane anaesthesia. To evaluate the reliability of the proposed method, the measured end-systolic and end-diastolic RVm were compared. Accuracy was evaluated by comparing preclinical RVm to ex vivo RV weight (RVw). We found that use of the self-correcting algorithm improved reliability compared with conventional segmentation. For clinical data, the limits of agreement (LOAs) were -1.8 ± 8.6g (self-correcting) vs. 5.8 ± 7.8g (conventional), and coefficients of variation (CoVs) were 7.0% (self-correcting) vs. 14.3% (conventional). For preclinical data, LOAs were 21 ± 46 mg (self-correcting) vs. 64 ± 89 mg (conventional), and CoVs were 9.0% (self-correcting) and 17.4% (conventional). Self-corrected RVm also showed better correspondence with the ex vivo RVw: LOAs were -5 ± 80 mg (self-correcting) vs. 94 ± 116 mg (conventional) in end-diastole and -26 ± 74 mg (self-correcting) vs. 31 ± 98 mg (conventional) in end-systole. The new self-correcting algorithm improves the reliability and accuracy of RVm measurements in both clinical and preclinical MRI. It is simple and easy to implement and does not require any additional MRI data.NEW & NOTEWORTHY Magnetic resonance imaging (MRI) of the right ventricle (RV) offers important diagnostic information, but the accuracy of this information is hampered by the complex geometry of the RV. In particular, the crescent shape of the RV renders it particularly vulnerable to partial-volume effects. We present a new, simple, self-correcting algorithm that can be applied to correct partial-volume effects in MRI-based RV mass estimation. The self-correcting algorithm offers improved reliability and accuracy compared with the conventional approach.

Regional right ventricular function in rats: a novel magnetic resonance imaging method for measurement of right ventricular strain.

The function of the right ventricle (RV) is linked to clinical outcome in many cardiovascular diseases, but its role in experimental heart failure remains largely unexplored due to difficulties in measuring RV function in vivo. We aimed to advance RV imaging by establishing phase-contrast MRI (PC-MRI) as a robust method for measuring RV function in rodents. A total of 46 Wistar-Hannover rats with left ventricular (LV) myocardial infarction and 10 control rats (sham) were examined 6 wk after surgery. Using a 9.4-T preclinical MRI system, we utilized PC-MRI to measure strain/strain rate in the RV free wall under isoflurane anesthesia. Cine MRI was used to measure RV volumes. LV end-diastolic pressure (LVEDP) was measured and used to identify pulmonary congestion. The infarct rats were divided into two groups: those with signs of pulmonary congestion (PC), with LVEDP ≥ 15 mmHg (n = 26) and those without signs of pulmonary congestion (NPC), with LVEDP < 15 mmHg (n = 20). The NPC rats exhibited preserved RV strains/strain rates, whereas the PC rats exhibited reduced strains/strain rates (26-48% lower than sham). Of the strain parameters, longitudinal strain and strain rate exhibited the highest correlations to LVEDP and lung weight (rho = 0.65-0.72, P < 0.001). Basal longitudinal strain was most closely associated with signs of pulmonary congestion and indexes of RV remodeling. Longitudinal RV strain had higher area under the curve than ejection fraction for detecting subtle RV dysfunction (area under the curve = 0.85 vs. 0.67). In conclusion, we show for the first time that global and regional RV myocardial strain can be measured robustly in rodents. Reduced RV strain was closely associated with indexes of pulmonary congestion and molecular markers of RV remodeling.NEW & NOTEWORTHY Global and regional right ventricular myocardial strain can be measured with high reproducibility and low interobserver variability in rodents using tissue phase mapping MRI. Reduced right ventricular strain was associated with indexes of pulmonary congestion and molecular markers of right ventricular remodeling. Regional strain in the basal myocardium was considerably higher than in the apical myocardium.

Accelerated magnetic resonance imaging tissue phase mapping of the rat myocardium using compressed sensing with iterative soft-thresholding.

INTRODUCTION: Tissue Phase Mapping (TPM) MRI can accurately measure regional myocardial velocities and strain. The lengthy data acquisition, however, renders TPM prone to errors due to variations in physiological parameters, and reduces data yield and experimental throughput. The purpose of the present study is to examine the quality of functional measures (velocity and strain) obtained by highly undersampled TPM data using compressed sensing reconstruction in infarcted and non-infarcted rat hearts. METHODS: Three fully sampled left-ventricular short-axis TPM slices were acquired from 5 non-infarcted rat hearts and 12 infarcted rat hearts in vivo. The datasets were used to generate retrospectively (simulated) undersampled TPM datasets, with undersampling factors of 2, 4, 8 and 16. Myocardial velocities and circumferential strain were calculated from all datasets. The error introduced from undersampling was then measured and compared to the fully sampled data in order to validate the method. Finally, prospectively undersampled data were acquired and compared to the fully sampled datasets. RESULTS: Bland Altman analysis of the retrospectively undersampled and fully sampled data revealed narrow limits of agreement and little bias (global radial velocity: median bias = -0.01 cm/s, 95% limits of agreement = [-0.16, 0.20] cm/s, global circumferential strain: median bias = -0.01%strain, 95% limits of agreement = [-0.43, 0.51] %strain, all for 4x undersampled data at the mid-ventricular level). The prospectively undersampled TPM datasets successfully demonstrated the feasibility of method implementation. CONCLUSION: Through compressed sensing reconstruction, highly undersampled TPM data can be used to accurately measure the velocity and strain of the infarcted and non-infarcted rat myocardium in vivo, thereby increasing experimental throughput and simultaneously reducing error introduced by physiological variations over time.

Caspase-1 induces smooth muscle cell growth in hypoxia-induced pulmonary hypertension.

Lung diseases with hypoxia are complicated by pulmonary hypertension, leading to heart failure and death. No pharmacological treatment exists. Increased proinflammatory cytokines are found in hypoxic patients, suggesting an inflammatory pathogenesis. Caspase-1, the effector of the inflammasome, mediates inflammation through activation of the proinflammatory cytokines interleukin (IL)-18 and IL-1ß. Here, we investigate inflammasome-related mechanisms that can trigger hypoxia-induced pulmonary hypertension. Our aim was to examine whether caspase-1 induces development of hypoxia-related pulmonary hypertension and is a suitable target for therapy. Wild-type (WT) and caspase-1-/- mice were exposed to 10% oxygen for 14 days. Hypoxic caspase-1-/- mice showed lower pressure and reduced muscularization in pulmonary arteries, as well as reduced right ventricular remodeling compared with WT. Smooth muscle cell (SMC) proliferation was reduced in caspase-1-deficient pulmonary arteries and in WT arteries treated with a caspase-1 inhibitor. Impaired inflammation was shown in hypoxic caspase-1-/- mice by abolished pulmonary influx of immune cells and lower levels of IL-18, IL-1ß, and IL-6, which were also reduced in the medium surrounding caspase-1 abrogated pulmonary arteries. By adding IL-18 or IL-1ß to caspase-1-deficient pulmonary arteries, SMC proliferation was retained. Furthermore, inhibition of both IL-6 and phosphorylated STAT3 reduced proliferation of SMC in vitro, indicating IL-18, IL-6, and STAT3 as downstream mediators of caspase-1-induced SMC proliferation in pulmonary arteries. Caspase-1 induces SMC proliferation in pulmonary arteries through the caspase-1/IL-18/IL-6/STAT3 pathway, leading to pulmonary hypertension in mice exposed to hypoxia. We propose that caspase-1 inhibition is a potential target for treatment of pulmonary hypertension.

Regional Dysfunction After Myocardial Infarction in Rats.

BACKGROUND: Detailed understanding of regional function after myocardial infarction (MI) is currently incomplete. We aimed at investigating regional myocardial strain and work in post-MI rats with and without heart failure. METHODS AND RESULTS: Six weeks after induction of MI, 62 male Wistar-Hannover rats with a range of infarct sizes, plus 14 sham-operated rats, were examined by cine and phase-contrast magnetic resonance imaging. After magnetic resonance imaging, the rats were catheterized, and left ventricular pressures were recorded. Regional strain and work were calculated from the magnetic resonance imaging and pressure data. On the basis of end-diastolic left ventricular pressure, 34 MI rats were classified as nonfailing (MINF) and 28 MI rats as failing (MICHF). In the region remote to the infarct, the MINF rats exhibited preserved strain and increased work compared with sham, whereas MICHF had reduced longitudinal strain and no increase in work in this region. In the noninfarcted region adjacent to the infarct, MICHF demonstrated substantially reduced work because of high levels of negative work. CONCLUSIONS: We have demonstrated a distinct difference in regional work between nonfailing and failing hearts after MI and offer novel insight into the relation between regional function and presence of congestion. Work analysis provided significant added value over strain analysis alone.

A semiautomatic method for rapid segmentation of velocity-encoded myocardial magnetic resonance imaging data.

PURPOSE: To develop a semiautomatic method for rapid segmentation of myocardial tissue phase mapping (TPM) data. METHODS: Manual segmentation of the myocardium was performed at end-diastole and end-systole. The points in both user-defined masks were then automatically tracked over the entire cardiac cycle using temporal integration of the velocity field. Paths that failed to visit both masks at the expected times were excluded, after which masks for all time points were generated automatically from the accepted paths. Midventricular and basal phase contrast TPM slices from 12 rats were segmented using the proposed method and fully manual segmentation. The results were compared using Dice's metric and Bland-Altman analysis, and interobserver variability was assessed. RESULTS: The semiautomatic method reduced the average user input time from 21 min to 1 min per slice. The Dice metrics between the methods were 0.88 ± 0.03 (midventricular) and 0.83 ± 0.06 (basal), and Bland-Altman limits of agreement of peak systolic and diastolic regional velocities were: midventricular: 0.05 ± 0.65 cm/s, -0.02 ± 0.42 cm/s, and -0.03 ± 0.40 cm/s (radial, tangential, longitudinal); basal: -0.04 ± 0.73 cm/s, 0.03 ± 0.60 cm/s, and -0.04 ± 0.48 cm/s (radial, tangential, longitudinal). Interobserver variability following semiautomatic segmentation was lower than for manual segmentation. CONCLUSION: The proposed method reduced the segmentation time substantially and exhibited well-preserved data quality and excellent interobserver limits of agreement. Magn Reson Med 78:1199-1207, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Elevated ventricular wall stress disrupts cardiomyocyte t-tubule structure and calcium homeostasis.

AIMS: Invaginations of the cellular membrane called t-tubules are essential for maintaining efficient excitation-contraction coupling in ventricular cardiomyocytes. Disruption of t-tubule structure during heart failure has been linked to dyssynchronous, slowed Ca(2+) release and reduced power of the heartbeat. The underlying mechanism is, however, unknown. We presently investigated whether elevated ventricular wall stress triggers remodelling of t-tubule structure and function. METHODS AND RESULTS: MRI and blood pressure measurements were employed to examine regional wall stress across the left ventricle of sham-operated and failing, post-infarction rat hearts. In failing hearts, elevated left ventricular diastolic pressure and ventricular dilation resulted in markedly increased wall stress, particularly in the thin-walled region proximal to the infarct. High wall stress in this proximal zone was associated with reduced expression of the dyadic anchor junctophilin-2 and disrupted cardiomyocyte t-tubular structure. Indeed, local wall stress measurements predicted t-tubule density across sham and failing hearts. Elevated wall stress and disrupted cardiomyocyte structure in the proximal zone were also associated with desynchronized Ca(2+) release in cardiomyocytes and markedly reduced local contractility in vivo. A causative role of wall stress in promoting t-tubule remodelling was established by applying stretch to papillary muscles ex vivo under culture conditions. Loads comparable to wall stress levels observed in vivo in the proximal zone reduced expression of junctophilin-2 and promoted t-tubule loss. CONCLUSION: Elevated wall stress reduces junctophilin-2 expression and disrupts t-tubule integrity, Ca(2+) release, and contractile function. These findings provide new insight into the role of wall stress in promoting heart failure progression.

Three-Directional Evaluation of Mitral Flow in the Rat Heart by Phase-Contrast Cardiovascular Magnetic Resonance.

PURPOSE: Determination of mitral flow is an important aspect in assessment of cardiac function. Traditionally, mitral flow is measured by Doppler echocardiography which suffers from several challenges, particularly related to the direction and the spatial inhomogeneity of flow. These challenges are especially prominent in rodents. The purpose of this study was to establish a cardiovascular magnetic resonance (CMR) protocol for evaluation of three-directional mitral flow in a rodent model of cardiac disease. MATERIALS AND METHODS: Three-directional mitral flow were evaluated by phase contrast CMR (PC-CMR) in rats with aortic banding (AB) (N = 7) and sham-operated controls (N = 7). Peak mitral flow and deceleration rate from PC-CMR was compared to conventional Doppler echocardiography. The accuracy of PC-CMR was investigated by comparison of spatiotemporally integrated mitral flow with left ventricular stroke volume assessed by cine CMR. RESULTS: PC-CMR portrayed the spatial distribution of mitral flow and flow direction in the atrioventricular plane throughout diastole. Both PC-CMR and echocardiography demonstrated increased peak mitral flow velocity and higher deceleration rate in AB compared to sham. Comparison with cine CMR revealed that PC-CMR measured mitral flow with excellent accuracy. Echocardiography presented significantly lower values of flow compared to PC-CMR. CONCLUSIONS: For the first time, we show that PC-CMR offers accurate evaluation of three-directional mitral blood flow in rodents. The method successfully detects alterations in the mitral flow pattern in response to cardiac disease and provides novel insight into the characteristics of mitral flow.

Assessment of regional myocardial work in rats.

BACKGROUND: Left ventricular (LV) motion and deformation is dependent on mechanical load and do therefore not reflect myocardial energy consumption directly. Regional myocardial work, however, constitutes a more complete assessment of myocardial function. METHODS AND RESULTS: Strain was measured using high-resolution phase-contrast MRI in 9 adult male rats with myocardial infarction (MI) and in 5 sham-operated control animals. Timing of LV valvular events and LV dimensions were evaluated by cine MRI. A separate cohort of 14 animals (MI/sham=9/5) underwent measurement of LV pressure concurrent with identification of valvular events by Doppler-echocardiography for the purpose of generating a standard LV pressure curve, normalized to valvular events. The infarctions were localized to the anterolateral LV wall. Combining strain with timing of valvular events and a measurement of peak arterial pressure, regional myocardial work could be calculated by applying the standard LV pressure curves. Cardiac output and stroke work was preserved in the MI hearts, suggesting a compensatory redistribution of myocardial work from the infarcted region to the viable tissue. In the septum, regional work was indeed increased in MI rats compared with sham (median work per unit long-axis length in a mid-ventricular slice: 241.2 [224.1-271.2] versus 137.2 [127.0-143.8] mJ/m; P<0.001). Myocardial work in infarcted regions was zero. Additionally, eccentric work was increased in the MI hearts. CONCLUSIONS: Phase-contrast MRI, in combination with measurement of peak arterial pressure and MRI-derived timing of valvular events, represent a noninvasive approach for estimation of regional myocardial work in rodents.

Unwrapping eddy current compensation: improved compensation of eddy current induced baseline shifts in high-resolution phase-contrast MRI at 9.4 Tesla.

PURPOSE: Phase-contrast MRI (PC-MRI) is a versatile tool allowing evaluation of in vivo motion, but is sensitive to eddy current induced phase offsets, causing errors in the measured velocities. In high-resolution PC-MRI, these offsets can be sufficiently large to cause wrapping in the baseline phase, rendering conventional eddy current compensation (ECC) inadequate. The purpose of this study was to develop an improved ECC technique (unwrapping ECC) able to handle baseline phase discontinuities. THEORY AND METHODS: Baseline phase discontinuities are unwrapped by minimizing the spatiotemporal standard deviation of the static-tissue phase. Computer simulations were used for demonstrating the theoretical foundation of the proposed technique. The presence of baseline wrapping was confirmed in high-resolution myocardial PC-MRI of a normal rat heart at 9.4 Tesla (T), and the performance of unwrapping ECC was compared with conventional ECC. RESULTS: Areas of phase wrapping in static regions were clearly evident in high-resolution PC-MRI. The proposed technique successfully eliminated discontinuities in the baseline, and resulted in significantly better ECC than the conventional approach. CONCLUSION: We report the occurrence of baseline phase wrapping in PC-MRI, and provide an improved ECC technique capable of handling its presence. Unwrapping ECC offers improved correction of eddy current induced baseline shifts in high-resolution PC-MRI.

Novel insight into the detailed myocardial motion and deformation of the rodent heart using high-resolution phase contrast cardiovascular magnetic resonance.

BACKGROUND: Phase contrast velocimetry cardiovascular magnetic resonance (PC-CMR) is a powerful and versatile tool allowing assessment of in vivo motion of the myocardium. However, PC-CMR is sensitive to motion related artifacts causing errors that are geometrically systematic, rendering regional analysis of myocardial function challenging. The objective of this study was to establish an optimized PC-CMR method able to provide novel insight in the complex regional motion and strain of the rodent myocardium, and provide a proof-of-concept in normal and diseased rat hearts with higher temporal and spatial resolution than previously reported. METHODS: A PC-CMR protocol optimized for assessing the motion and deformation of the myocardium in rats with high spatiotemporal resolution was established, and ten animals with different degree of cardiac dysfunction underwent examination and served as proof-of-concept. Global and regional myocardial velocities and circumferential strain were calculated, and the results were compared to five control animals. Furthermore, the global strain measurements were validated against speckle-tracking echocardiography, and inter- and intrastudy variability of the protocol were evaluated. RESULTS: The presented method allows assessment of regional myocardial function in rats with high level of detail; temporal resolution was 3.2 ms, and analysis was done using 32 circumferential segments. In the dysfunctional hearts, global and regional function were distinctly altered, including reduced global peak values, increased regional heterogeneity and increased index of dyssynchrony. Strain derived from the PC-CMR data was in excellent agreement with echocardiography (r = 0.95, p < 0.001; limits-of-agreement -0.02 ± 3.92%strain), and intra- and interstudy variability were low for both velocity and strain (limits-of-agreement, radial motion: 0.01 ± 0.32 cm/s and -0.06 ± 0.75 cm/s; circumferential strain: -0.16 ± 0.89%strain and -0.71 ± 1.67%strain, for intra- and interstudy, respectively). CONCLUSION: We demonstrate, for the first time, that PC-CMR enables high-resolution evaluation of in vivo circumferential strain in addition to myocardial motion of the rat heart. In combination with the superior geometric robustness of CMR, this ultimately provides a tool for longitudinal studies of regional function in rodents with high level of detail.

Improved MR phase-contrast velocimetry using a novel nine-point balanced motion-encoding scheme with increased robustness to eddy current effects.

Phase-contrast MRI (PC-MRI) velocimetry is a noninvasive, high-resolution motion assessment tool. However, high motion sensitivity requires strong motion-encoding magnetic gradients, making phase-contrast-MRI prone to baseline shift artifacts due to the generation of eddy currents. In this study, we propose a novel nine-point balanced velocity-encoding strategy, designed to be more accurate in the presence of strong and rapidly changing gradients. The proposed method was validated using a rotating phantom, and its robustness and precision were explored and compared with established approaches through computer simulations and in vivo experiments. Computer simulations yielded a 39-57% improvement in velocity-noise ratio (corresponding to a 27-33% reduction in measurement error), depending on which method was used for comparison. Moreover, in vivo experiments confirmed this by demonstrating a 26-53% reduction in accumulated velocity error over the R-R interval. The nine-point balanced phase-contrast-MRI-encoding strategy is likely useful for settings where high spatial and temporal resolution and/or high motion sensitivity is required, such as in high-resolution rodent myocardial tissue phase mapping.

An analysis of deformation-dependent electromechanical coupling in the mouse heart.

To investigate the effects of the coupling between excitation and contraction on whole-organ function, we have developed a novel biophysically based multiscale electromechanical model of the murine heart. Through comparison with a comprehensive in vivo experimental data set, we show good agreement with pressure and volume measurements at both physiological temperatures and physiological pacing frequencies. This whole-organ model was used to investigate the effects of material and haemodynamic properties introduced at the tissue level, as well as emergent function of our novel cell contraction model. Through a comprehensive sensitivity analysis at both the cellular and whole organ level, we demonstrate the sensitivity of the model's results to its parameters and the constraining effect of experimental data. These results demonstrate the fundamental importance of length- and velocity-dependent feedback to the cellular scale for whole-organ function, and we show that a strong velocity dependence of tension is essential for explaining the differences between measured single cell tension and whole-organ pressure transients.