Emil K.S. Espe

An analysis of deformation‐dependent electromechanical coupling in the mouse heart

•  The amount of force generated by heart cells is strongly influenced by feedback from the deformation of cardiac tissue, both from the changes in cell length and the rate at which cells are stretched. •  We analysed the effect these cellular mechanisms have on whole heart function by making a computational model of mouse heart cells, and embedding this cellular model into a representation of the heart. •  Unlike previous murine models, this model represents the heart at both body temperature and the high heart rates seen in these animals, allowing us to directly compare results from our computational model with experimental measurements. •  Results show that effects from the rate of stretch are especially important for explaining the large differences observed between force generated by isolated cells and pressure measured experimentally. •  The model also provides an important framework for future research focused on interpreting results from genetic manipulation experiments in mice.

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 Ca2+ 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 Ca2+ 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, Ca2+ release, and contractile function. These findings provide new insight into the role of wall stress in promoting heart failure progression.

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. Magn Reson Med, 2013.

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.

IL-18 neutralization during alveolar hypoxia improves left ventricular diastolic function in mice.

In patients, an association exists between pulmonary diseases and diastolic dysfunction of the left ventricle (LV). We have previously shown that alveolar hypoxia in mice induces LV diastolic dysfunction and that mice exposed to hypoxia have increased levels of circulating interleukin‐18 (IL‐18), suggesting involvement of IL‐18 in development of diastolic dysfunction. IL‐18 binding protein (IL‐18BP) is a natural inhibitor of IL‐18. In this study, we hypothesized that neutralization of IL‐18 during alveolar hypoxia would improve LV diastolic function.

Unwrapping eddy current compensation: Improved compensation of eddy current induced baseline shifts in high-resolution phase-contrast MRI at 9.4 tesla

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.

Noninvasive stratification of postinfarction rats based on the degree of cardiac dysfunction using magnetic resonance imaging and echocardiography

The myocardial infarction (MI) rat model plays a crucial role in modern cardiovascular research, but the inherent heterogeneity of this model represents a challenge. We sought to identify subgroups among the post-MI rats and establish simple noninvasive stratification protocols for such subgroups. Six weeks after induction of MI, 49 rats underwent noninvasive examinations using magnetic resonance imaging (MRI) and echocardiography. Twelve sham-operated rats served as controls. Increased end-diastolic left ventricular (LV) pressure and lung weight served as indicators for congestive heart failure (CHF). A clustering algorithm using 13 noninvasive and invasive parameters was used to identify distinct groups among the animals. The cluster analysis revealed four distinct post-MI phenotypes; two without congestion but with different degree of LV dilatation, and two with different degree of congestion and right ventricular (RV) affection. Among the MRI parameters, RV mass emerged as robust noninvasive marker of CHF with 100% specificity/sensitivity. Moreover, LV infarct size and RV ejection fraction further predicted subgroup among the non-CHF and CHF rats with excellent specificity/sensitivity. Of the echocardiography parameters, left atrial diameter predicted CHF. Moreover, LV end-diastolic diameter predicted the subgroups among the non-CHF rats. We propose two simple noninvasive schemes to stratify post-MI rats, based on the degree of heart failure; one for MRI and one for echocardiography.NEW & NOTEWORTHY In vivo phenotyping of rats is essential for robust and reliable data. Here, we present two simple noninvasive schemes for the stratification of postinfarction rats based on the degree of heart failure: one using magnetic resonance imaging and one based on echocardiography.

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.

Regional diastolic dysfunction in post-infarction heart failure: role of local mechanical load and SERCA expression

Abstract Aims Regional heterogeneities in contraction contribute to heart failure with reduced ejection fraction (HFrEF). We aimed to determine whether regional changes in myocardial relaxation similarly contribute to diastolic dysfunction in post-infarction HFrEF, and to elucidate the underlying mechanisms. Methods and results Using the magnetic resonance imaging phase-contrast technique, we examined local diastolic function in a rat model of post-infarction HFrEF. In comparison with sham-operated animals, post-infarction HFrEF rats exhibited reduced diastolic strain rate adjacent to the scar, but not in remote regions of the myocardium. Removal of Ca2+ within cardiomyocytes governs relaxation, and we indeed found that Ca2+ transients declined more slowly in cells isolated from the adjacent region. Resting Ca2+ levels in adjacent zone myocytes were also markedly elevated at high pacing rates. Impaired Ca2+ removal was attributed to a reduced rate of Ca2+ sequestration into the sarcoplasmic reticulum (SR), due to decreased local expression of the SR Ca2+ ATPase (SERCA). Wall stress was elevated in the adjacent region. Using ex vivo experiments with loaded papillary muscles, we demonstrated that high mechanical stress is directly linked to SERCA down-regulation and slowing of relaxation. Finally, we confirmed that regional diastolic dysfunction is also present in human HFrEF patients. Using echocardiographic speckle-tracking of patients enrolled in the LEAF trial, we found that in comparison with controls, post-infarction HFrEF subjects exhibited reduced diastolic train rate adjacent to the scar, but not in remote regions of the myocardium. Conclusion Our data indicate that relaxation varies across the heart in post-infarction HFrEF. Regional diastolic dysfunction in this condition is linked to elevated wall stress adjacent to the infarction, resulting in down-regulation of SERCA, disrupted diastolic Ca2+ handling, and local slowing of relaxation.

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

To develop a semiautomatic method for rapid segmentation of myocardial tissue phase mapping (TPM) data.