Abstract-Left ventricular (LV) remodeling leads to congestive heart failure and is a main determinant of morbidity and mortality following myocardial infarction. Therapeutic options to prevent LV remodeling are limited, which necessitates the exploration of alternative therapeutic targets. Toll-like receptors (TLRs) serve as pattern recognition receptors within the innate immune system. Activation of TLR4 results in an inflammatory response and is involved in extracellular matrix degradation, both key processes of LV remodeling following myocardial infarction. To establish the role of TLR4 in postinfarct LV remodeling, myocardial infarction was induced in wild-type BALB/c mice and TLR4-defective C3H-Tlr4 LPSϪd mice. Without affecting infarct size, TLR4 defectiveness reduced the extent of LV remodeling (end-diastolic volume: 103.7Ϯ6.8 L versus 128.5Ϯ5.7 L; PϽ0.01) and preserved systolic function (ejection fraction: 28.2Ϯ3.1% versus 16.6Ϯ1.3%; PϽ0.01), as assessed by MRI. In the noninfarcted area, interstitial fibrosis, and myocardial hypertrophy were reduced in C3H-Tlr4LPSϪd mice. In the infarcted area, however, collagen density was increased, which was accompanied by fewer macrophages, reduced inflammation regulating cytokine expression levels (interleukin [IL]-1␣, IL-2, IL-4, IL-5, IL-6, IL-10, IL-17, tumor necrosis factor-␣, interferon-␥, granulocyte/macrophage colony-stimulating factor), and reduced matrix metalloproteinase-2 (4684Ϯ515 versus 7573Ϯ611; Pϭ0.002) and matrix metalloproteinase-9 activity (76.0Ϯ14.3 versus 168.0Ϯ36.2; Pϭ0.027). These data provide direct evidence for a causal role of TLR4 in postinfarct maladaptive LV remodeling, probably via inflammatory cytokine production and matrix degradation. TLR4 may therefore constitute a novel target in the treatment of ischemic heart failure.

Myotonic dystrophy (DM) is commonly associated with CTG repeat expansions within the gene for DM-protein kinase (DMPK). The effect of altered expression levels of DMPK, which is ubiquitously expressed in all muscle cell lineages during development, was examined by disrupting the endogenous Dmpk gene and overexpressing a normal human DMPK transgene in mice. Nullizygous (-/-) mice showed only inconsistent and minor size changes in head and neck muscle fibres at older age, animals with the highest DMPK transgene expression showed hypertrophic cardiomyopathy and enhanced neonatal mortality. However, both models lack other frequent DM symptoms including the fibre-type dependent atrophy, myotonia, cataract and male-infertility. These results strengthen the contention that simple loss- or gain-of-expression of DMPK is not the only crucial requirement for development of the disease.

AimsRight ventricular (RV) dysfunction is a major determinant of long-term morbidity and mortality in congenital heart disease. The right ventricle (RV) is genetically different from the left ventricle (LV), but it is unknown as to whether this has consequences for the cellular responses to abnormal loading conditions. In the LV, calcineurinactivation is a major determinant of pathological hypertrophy and an important target for therapeutic strategies. We studied the functional and molecular adaptation of the RV in mouse models of pressure and volume load, focusing on calcineurin-activation. Methods and resultsMice were subjected to pulmonary artery banding (PAB), aorto-caval shunt (Shunt), or sham surgery (Control). Four weeks later, mice were functionally evaluated with cardiac magnetic resonance imaging, pressure measurements, and voluntary cage wheel exercise. Right ventricular hypertrophy and calcineurin-activation were assessed after sacrifice. Mice with increased pressure load (PAB) or volume load (Shunt) of the RV developed similar degrees of hypertrophy, yet revealed different functional and molecular adaptation. Pulmonary artery banding increased expression of Modulatory-Calcineurin-Interacting-Protein 1 (MCIP1), indicating calcineurin-activation, and the ratio of beta/alphaMyosin Heavy Chain (MHC). In addition, PAB reduced exercise capacity and induced moderate RV dilatation with normal RV output at rest. In contrast, Shunt did not increase MCIP1 expression, and only moderately increased beta/alpha-MHC ratio. Shunt did not affect exercise capacity, but increased RV volumes and output at rest. ConclusionsPressure and volume load induced different functional and molecular adaptations in the RV. These results may have important consequences for therapeutic strategies to prevent RV failure in the growing population of adults with congenital heart disease.--

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We have developed a mouse severe combined immunodeficient (SCID) model of myocardial infarction based on permanent coronary artery occlusion that allows long-term functional analysis of engrafted human embryonic stem cell-derived cardiomyocytes, genetically marked with green fluorescent protein (GFP), in the mouse heart. We describe methods for delivery of dissociated cardiomyocytes to the left ventricle that minimize scar formation and visualization and validation of the identity of the engrafted cells using the GFP emission spectrum, and histological techniques compatible with GFP epifluorescence, for monitoring phenotypic changes in the grafts in vivo. In addition, we describe how magnetic resonance imaging can be adapted for use in mice to monitor cardiac function non-invasively and repeatedly. The model can be adapted to include multiple control or other cell populations. The procedure for a cohort of six mice can be completed in a maximum of 13 weeks, depending on follow-up, with 30 h of hands-on time.