MRI of mouse heart failure

Heart failure (HF) is the inability of the heart to pump blood at a rate that satisfies the peripheral needs and is a final consequence of many pathologies. Left ventricular (LV) pressure overload and myocardial infarction are amongst the most important causes of HF. Common and important hallmarks of HF are myocardial hypertrophy, fibrosis, vascular adaptation and metabolic remodeling. The role of cardiac magnetic resonance (CMR) as a diagnostic tool for HF is rapidly increasing. The prognostic value of important measures of LV function such as ejection fraction, however, is limited. To improve diagnostic relevance and risk stratification additional MR imaging and spectroscopy techniques are therefore highly desired. For that, preclinical research in mouse models plays an important role. This goal of this thesis was to apply multiple, novel MR imaging methods and phosphorous 31PMR spectroscopy for the evaluation of mouse HF, with a focus on myocardial hypertrophy, fibrosis, perfusion and LV energy status. These techniques are part of an ever extending toolbox for mouse CMR that allows the researcher to perform a multi-parametric assessment of myocardial tissue status. Preferably, a time-efficient protocol is constructed from all these tools, which is tailored for a particular HF phenotype and yields the relevant, decisive features of the stage of development towards HF. After successful proof-of-concept studies in mice, these techniques could be translated for clinical use. Ultimately, these techniques might then contribute to improved diagnostic accuracy and a better characterization of the tissue status, new (surrogate) end-points to evaluate the success of therapies and interventions, and perhaps may even provide better prognostic markers for the disease course. The transverse aortic constriction (TAC) mouse model was used throughout this thesis as it is an important model of pressure overload induced hypertrophy and HF. Since the TAC model was first described, it has been extensively used to study various facets of pressure overload induced LV adaptation. In Chapter 2 we characterized cardiac function and morphology in a mild and severe TAC model. Mice underwent repeated measurements to evaluate the progression of cardiac parameters over time. The mild TAC mice developed a stage of compensated LV hypertrophy and mildly impaired LV function. No progressive deterioration of myocardial function was observed over time and LV maladaptation did not result in pulmonary remodeling and RV failure. LV function and morphology in severe TAC mice, on the other hand, progressively deteriorated over time resulting in overt decompensated hypertrophy, which was also indicated by profound pulmonary remodeling and impaired RV function. A repeatable method for quantitative, first-pass perfusion MRI of the mouse heart based on a dual-bolus approach was described in Chapter3. A non-saturated arterial input function was acquired from a low-dose containing Gd(DTPA)2- prebolus. The myocardial tissue response was measured from a separate high-dose full-bolus infusion. Perfusion (ml min-1 g-1) was quantified using a Fermi constrained deconvolution of the myocardial tissue response with the arterial input function. This calculation critically depends on linearity of the measured MR signal intensity with Gd(DTPA)2- concentration in the LV lumen during the prebolus and in the myocardial wall during the full-bolus. In separate experiments these assumptions were proven to be valid for our experimental conditions. Interestingly, this assumption was to the best of our knowledge never demonstrated in vivo, although Weber et al. confirmed the appropriateness of this assumption for quantitative first-pass perfusion measurements in the human heart using phantom experiments. The first-pass perfusion method was used in Chapter 4 to study myocardial perfusion in TAC mice, which was considerably decreased as compared to perfusion in control mice. Importantly, the relationship between perfusion and LV morphology and function was studied. Clear correlations were obtained between a decreased perfusion in TAC mice and the indices of LV function and morphology, e.g., LV ejection fraction, volumes as well as LV mass. Although group-averaged perfusion values in TAC mice did not change between measurements in the longitudinal study, these results revealed that with an ensuing hypertrophic growth and concomitantly declining LV function (Chapter 2) perfusion gradually diminishes. Current MRI techniques for the quantification of diffuse myocardial fibrosis suffer from severe limitations. In Chapter 5 ultra short echo time (UTE) MRI was used to study replacement and diffuse fibrosis in the ex vivo and in vivo mouse heart. Here, the MI mouse model was also used as it results in the formation of a spatially confined, collagenous scar providing an ideal model for proof-of-principle purposes. Subtraction of short- and long-TE images resulted in images highlighting tissue with short T2*, such as collagen. Indeed, a good correlation was obtained between the relative infarct volume as determined from histology and ex vivo UTE MRI. UTE MRI also resulted in signal differences between control and TAC hearts, which were related to the amount of collagen present in the hearts. Cardiovascular UTE MRI may thus provide a means for the assessment of diffuse fibrosis based on endogenous tissue contrast. Impaired myocardial energetics are thought to play an important role in HF. Chapter 6 describes 3D Image Selected In vivo Spectroscopy (ISIS) for single-voxel localized 31P-MRS of the in vivo mouse heart. From the resulting spectra the phosphocreatine-to-ATP (PCr/¿-ATP) ratio was quantified as a measure for myocardial energy status. When mice showed a markedly impaired LV systolic function and myocardial hypertrophy 7 weeks after TAC, PCr/ATP was approximately 25% lower 7 weeks as compared to control mice. Multiple studies have pointed to the possible predictive value of PCr/ATP, an important measure for myocardial energy status, for subsequent maladaptive ventricular remodeling. It is unclear though if PCr/ATP measured during the first stage of the remodeling process also predicts consecutive maladaptation. In Chapter 7 the hypothesis was therefore tested that PCr/ATP measured at the day of TAC or four days thereafter predicts subsequent remodeling. Such a relation could, however, not be established. Clear relations were obtained, on the other hand, between LV function and morphology four days after TAC and seven weeks, pointing to the importance of the severity of the initial pressure overload for maladaptive cardiac remodeling. In addition, these experiments showed an apparent decrease of PCr/ATP already at the day of TAC, whereas PCr/ATP four days after TAC was significantly decreased, pointing to the first signs of an impaired myocardial energy status

Phenotyping of left and right ventricular function in mouse models of compensated hypertrophy and heart failure with cardiac MRI

Background: Left ventricular (LV) and right ventricular (RV) function have an important impact on symptom occurrence, disease progression and exercise tolerance in pressure overload-induced heart failure, but particularly RV functional changes are not well described in the relevant aortic banding mouse model. Therefore, we quantified time-dependent alterations in the ventricular morphology and function in two models of hypertrophy and heart failure and we studied the relationship between RV and LV function during the transition from hypertrophy to heart failure. Methods: MRI was used to quantify RV and LV function and morphology in healthy (n = 4) and sham operated (n = 3) C57BL/6 mice, and animals with a mild (n = 5) and a severe aortic constriction (n = 10). Results: Mice subjected to a mild constriction showed increased LV mass (P,0.01) and depressed LV ejection fraction (EF) (P,0.05) as compared to controls, but had similar RVEF (P.0.05). Animals with a severe constriction progressively developed LV hypertrophy (P,0.001), depressed LVEF (P,0.001), followed by a declining RVEF (P,0.001) and the development of pulmonary remodeling, as compared to controls during a 10-week follow-up. Myocardial strain, as a measure for local cardiac function, decreased in mice with a severe constriction compared to controls (P,0.05). Conclusions: Relevant changes in mouse RV and LV function following an aortic constriction could be quantified using MRI. The well-controlled models described here open opportunities to assess the added value of new MRI techniques for the diagnosis of heart failure and to study the impact of new therapeutic strategies on disease progression and symptom occurrence

Deep tissue injury : how deep is our understanding?

No abstract

Phenotyping of Left and Right Ventricular Function in Mouse Models of Compensated Hypertrophy and Heart Failure with Cardiac MRI

Background: Left ventricular (LV) and right ventricular (RV) function have an important impact on symptom occurrence, disease progression and exercise tolerance in pressure overload-induced heart failure, but particularly RV functional changes are not well described in the relevant aortic banding mouse model. Therefore, we quantified time-dependent alterations in the ventricular morphology and function in two models of hypertrophy and heart failure and we studied the relationship between RV and LV function during the transition from hypertrophy to heart failure. Methods: MRI was used to quantify RV and LV function and morphology in healthy (n = 4) and sham operated (n = 3) C57BL/6 mice, and animals with a mild (n = 5) and a severe aortic constriction (n = 10). Results: Mice subjected to a mild constriction showed increased LV mass (P0.05). Animals with a severe constriction progressively developed LV hypertrophy (P<0.001), depressed LVEF (P<0.001), followed by a declining RVEF (P<0.001) and the development of pulmonary remodeling, as compared to controls during a 10-week follow-up. Myocardial strain, as a measure for local cardiac function, decreased in mice with a severe constriction compared to controls (P<0.05). Conclusions: Relevant changes in mouse RV and LV function following an aortic constriction could be quantified using MRI. The well-controlled models described here open opportunities to assess the added value of new MRI techniques for the diagnosis of heart failure and to study the impact of new therapeutic strategies on disease progression and symptom occurrence

Myocardial perfusion MRI shows impaired perfusion of the mouse hypertrophic left ventricle

There is growing consensus that myocardial perfusion deficits play a pivotal role in the transition from compensated to overt decompensated hypertrophy. The purpose of this study was to systematically study myocardial perfusion deficits in the highly relevant model of pressure overload induced hypertrophy and heart failur

Retrieving unobserved consideration sets from household panel data

The authors propose a new model to capture unobserved consideration from discrete choice data. This approach allows for unobserved dependence in consideration among brands, easily copes with many brands, and accommodates different effects of the marketing mix on consideration and choice as well as unobserved consumer heterogeneity in both processes. An important goal of this study is to establish validity of the existing practice to infer consideration sets from observed choices in panel data. The authors show with experimental data that underlying consideration sets can be reliably retrieved from choice data alone and that consideration is positively affected by display and shelf space. Next, the model is applied to Information Resources Inc. panel data. The findings suggest that promotion effects are larger when they are included in the consideration stage of the two-stage model than in a single-stage model. The authors also find that consideration covaries across brands and that covariation is mainly driven by unobserved consumer heterogeneity. Finally, the authors show the implications of the model for promotion planning relative to a more standard model of choice