We study mechanisms of cardiac myocyte dysfunction and cellular remodeling in diseased hearts. Cardiac remodeling is a maladaptive process in response to cardiac stressors (e.g. ischemia, hypertension) or systemic disease states (such as diabetes, chronic kidney disease). Alterations in size, geometry and function of the heart during cardiac remodeling are often progressive and may be accompagnied by heart failure and arrhythmias.
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We study mechanisms of cardiac myocyte dysfunction and cellular remodeling in diseased hearts. Cardiac remodeling is a maladaptive process in response to cardiac stressors (e.g. ischemia, hypertension) or systemic disease states (such as diabetes, chronic kidney disease). Alterations in size, geometry and function of the heart during cardiac remodeling are often progressive and may be accompagnied by heart failure and arrhythmias. The clinical syndromes of heart failure with reduced (HFrEF) or preserved (HFpEF) ejection fraction comprise a wide range of disease etiologies and disease stages. Our aim is to identify and characterize early cellular changes and investigate new pharmacological approaches to improve or preserve function and prevent arrhythmias.
In the center of our research are signaling pathways which are related to alterations in Ca2+ or Na+ within the cardiac myocytes. Ca2+ is a mediator for diverse cardiomyocyte functions (contraction, electrical activity, metabolism, gene regulation) and is highly regulated in intracellular microdomains (Figure 1)
In ventricular cardiac myocytes T-tubules (Fig.2) give rise to functional microdomains throughout the cell.
Fig. 2: 3D reconstruction of a live ventricular cardiomyocyte (confocal laser scanning, dye: Di8-ANEPPS) [play wide]
Mechanisms of Ca2+-Mediated Diastolic Dysfunction
Intracellular Ca2+ release is triggered by the action potential throughout the cell. However, in diseased hearts, intracellular Ca2+ release may be dyssynchronous related to T-tubule remodeling (Heinzel et al. 2008). We have shown that in failing hearts Ca2+ removal from the cytosol is also dyssynchronous and related to slower relaxation of the diseased cardiomyocytes, and this can be pharmacologically modulated (Hohendanner 2013). We also demonstrated intra- and intercellular Ca2+ dyssynchrony in the whole heart using fast 2D spinning disk confocal microscopy. We are currently investigating mechanisms and potential therapeutic targets related to this novel contractile modality.
We also investigate mechanisms of contractile dysfunction in models of heart failure with preserved ejection fraction, where Ca2+ transients are altered.
Arrhythmogenic Ca2+ release
Spontaneous local Ca2+ release from the intracellular store (sarcoplasmic reticulum) can trigger cellular depolarizations as the basis for arrhythmias. We visualize this intracellular Ca2+ leak through the ryanodine receptor (Ca2+ sparks and waves) by fast confocal laser line scanning microscopy.
Increased intracellular [Ca2+] is exported from the cytosol by the sarcolemmal Na+/Ca2+ exchanger (NCX), which depolarizes the cell. The ryanodine receptor Ca2+ leak and the NCX may be targets for new antiarrhythmic therapies. We examine related signaling and its modulation.
Cardiac Cellular Function in Diseased Human Hearts
We regularily obtain small human myocardial tissue samples from the operating room that would normally be discarded . We perform functional measurements (force, arrhythmias) in small muscle strips and in isolated myocardium. We could show that reducing intracellular Ca2+ leak improves diastolic function in human myocardium (Sacherer et al. 2012).
We also have shown in isolated human cardiomyocytes that the removal of Ca2+ from the cytosol that initiates diastole is locally regulated and may become more dyssynchronous in diseased hearts (Hohendanner et al. 2013). We currently study the underlying mechanisms.
Cardiomyocyte Hypertrophic Signaling
Ca2+ is not only involved in excitation-contraction coupling and arryhthmias but also regulates cardiomyocyte metabolism, cell death (apoptosis) and gene regulation (excitation-transcription coupling). Alteration in intracellular Ca2+ (and Na+-) regulation can trigger and promote cardiac remodeling and heart failure. We examine Ca2+-dependent hypertrophic signaling pathways in response to different humoral and mechanical triggers of cardiac remodeling. Using qPCR, Western blot and immunocytochemistry in freshly isolated cardiomyocytes and primary cardiomyocyte cultures we quantify time- and etiology-dependent gene regulation and subcellular translocation in response to established and also emergent hypertrophic triggers.