Heart failure is a common, complex condition with a poor prognosis and increasing incidence. The syndrome of heart failure comprises changes in electrophysiology, contraction and energy metabolism. This complexity, and the interaction of the clinical syndrome with very frequently concurrent medical conditions such as diabetes, means that animal modelling of heart failure is difficult. The current animal models of heart failure in common use do not address several important clinical problems. There have been major recent advances in the understanding of cardiac biology in the healthy and failing myocardium, but these are, as yet, unmatched by advances in therapeutics. Arguably, the development of new animal models of heart failure, or at least adaptation of existing models, will be necessary to fully translate scientific advances in this area into new drugs. This review outlines the mouse models of heart failure in common usage today, and discusses how adaptations in these models may allow easier translation of animal experimentation into the clinical arena.

Cardiomyocytes are vulnerable to hypoxia in the adult, but adapted to hypoxia in utero. Current understanding of endogenous cardiac oxygen sensing pathways is limited. Myocardial oxygen consumption is determined by regulation of energy metabolism, which shifts from glycolysis to lipid oxidation soon after birth, and is reversed in failing adult hearts, accompanying re-expression of several “fetal” genes whose role in disease phenotypes remains unknown. Here we show that hypoxia-controlled expression of the transcription factor Hand1 determines oxygen consumption by inhibition of lipid metabolism in the fetal and adult cardiomyocyte, leading to downregulation of mitochondrial energy generation. Hand1 is under direct transcriptional control by HIF1α. Transgenic mice prolonging cardiac Hand1 expression die immediately following birth, failing to activate the neonatal lipid metabolising gene expression programme. Deletion of Hand1 in embryonic cardiomyocytes results in premature expression of these genes. Using metabolic flux analysis, we show that Hand1 expression controls cardiomyocyte oxygen consumption by direct transcriptional repression of lipid metabolising genes. This leads, in turn, to increased production of lactate from glucose, decreased lipid oxidation, reduced inner mitochondrial membrane potential, and mitochondrial ATP generation. We found that this pathway is active in adult cardiomyocytes. Up-regulation of Hand1 is protective in a mouse model of myocardial ischaemia. We propose that Hand1 is part of a novel regulatory pathway linking cardiac oxygen levels with oxygen consumption. Understanding hypoxia adaptation in the fetal heart may allow development of strategies to protect cardiomyocytes vulnerable to ischaemia, for example during cardiac ischaemia or surgery. Regulation of oxygen usage in cardiomyocytes is of great medical interest, because adult cardiac tissue is extremely vulnerable to hypoxia during myocardial infarction and cardiac surgery. While some progress has been made toward protecting cardiomyocytes from hypoxia in these circumstances, it has been limited by a lack of understanding of endogenous oxygen-sensing pathways. In contrast to adult cardiac tissue, embryonic cardiomyocytes are highly resistant to hypoxia, although the mechanisms underlying this have hitherto been unclear. Using mice we show that the transcription factor Hand1 is expressed at high levels in the fetal heart, under direct control of HIF1α signaling, a pathway well known to respond to hypoxia. We show that Hand1 expression decreases at birth as the neonate is exposed to higher levels of oxygen. By experimentally increasing Hand1 expression in the neonatal heart, we see lower oxygen consumption in cardiomyocytes and this is caused by Hand1 repressing key regulatory genes involved in cardiomyocyte lipid metabolism. This has the effect of decreasing mitochondrial ATP generation via the tricarboxylic acid cycle. Furthermore, we show that increasing Hand1 expression in adult transgenic hearts is protective against myocardial infarction, suggesting that a hypoxia–Hand1 pathway may also be of importance in the adult heart.

M2 muscarinic acetylcholine receptors modulate cardiac rhythm via regulation of the inward potassium current. To increase our understanding of M2 receptor physiology we used Total Internal Reflection Fluorescence Microscopy to visualize individual receptors at the plasma membrane of transformed CHO(M2) cells, a cardiac cell line (HL-1), primary cardiomyocytes and tissue slices from pre- and post-natal mice. Receptor expression levels between individual cells in dissociated cardiomyocytes and heart slices were highly variable and only 10% of murine cardiomyocytes expressed muscarinic receptors. M2 receptors were evenly distributed across individual cells and their density in freshly isolated embryonic cardiomyocytes was ~1μm(-2), increasing at birth (to ~3μm(-2)) and decreasing back to ~1μm(-2) after birth. M2 receptors were primarily monomeric but formed reversible dimers. They diffused freely at the plasma membrane, moving approximately 4-times faster in heart slices than in cultured cardiomyocytes. Knowledge of receptor density and mobility has allowed receptor collision rate to be modeled by Monte Carlo simulations. Our estimated encounter rate of 5-10 collisions per second, may explain the latency between acetylcholine application and GIRK channel opening.

Isolated ventricular non-compaction is an increasingly commonly diagnosed myocardial disorder characterised by excessive and prominent trabeculation of the morphologically left, and occasionally the right, ventricle. This is associated with high rates of thromboembolism, cardiac failure, and cardiac arrhythmia. Recent improvements in understanding the embryonic processes underlying ventricular formation have led to the hypothesis that ventricular non-compaction is due to a failure of normal ventriculogenesis, leading to abnormal myocardium which may present clinically many years later. Experimental work in animal models provides several candidate transcription factors and signalling molecules that could, in theory, cause ventricular non-compaction if disrupted.

Summary: The pathology of sudden infant death syndrome (SIDS) is poorly understood. Many risk factors, including hypoxia, have been identified. Prolongation of the ECG QTc interval is associated with elevated risk of SIDS but its aetiology in most cases remains unknown. We have characterised ECG changes in the newborn mouse in the hours and days following birth. There was a steady increase in heart rate alongside significant decreases in QTc interval, QRS duration and QTc dispersion over the first 10 postnatal days. Birth into hypoxia (10% FiO2) prevented electrocardiac maturation, downregulated cardiac ion-channel expression and led to neonatal death. We found that risk of death decreased with increasing age of exposure to hypoxia. Genetic elevation of cardiac hypoxia-signalling after birth in αMHC-Cre::VHLfl/fl mice also prevented electrocardiographic maturation, leading to arrhythmia and death before weaning. Immunohistochemistry and western blotting revealed internalisation and dephosphorylation of Connexin43. We conclude that increased ambient oxygen concentration after birth drives maturation of the cardiac electrical conduction system, failure of which leads to aberrant ion channel and Connexin43 expression and predisposes to arrhythmia and sudden death. This is consistent with known risk factors of SIDS and provides a link between neonatal hypoxia, ECG abnormalities and sudden death.