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Dr. Stephan E Lehnart,
This basic sciences session about changes of specialized membrane structures of heart cells (cardiac myocytes) and recent insight in excitation-contraction coupling in heart failure, was associated with keen questions from the auditorium and enthusiastic discussions. In addition, Prof. Karin Sipido announced a spotlight issue of the journal Cardiovascular Research on this topic due to the eminent importance in heart failure (see announcement: Cardiovasc Res 2012, 95(4): NP doi:10.1093/cvr/cvs267 ).
Prof Sipido (Leuven) introduced the concept how sarcolemmal membrane disorganization through T-tubule changes may lead to dyssynchrony of intracellular calcium release. While synchrony of calcium release is an essential characteristic of healthy cells, loss of synchrony occurs during myocyte remodeling in heart failure. Such dyssynchrony may involve key calcium transport proteins (the L-type calcium channel, the sodium/calcium exchanger, and the intracellular calcium release channel/ryanodine receptor). To approximate the human organ physiology, a porcine model of ischemic cardiomyopathy (stent occlusion of coronary artery for 6 weeks) was investigated. Confocal calcium imaging in isolated pig myocytes showed subcellular loss of calcium release synchronization concomitant with T-tubule changes. In contrast, in mouse hearts with myocardial infarcts the altered T-tubule density could be reversed through exercise training. As disease mechanism, ryanodine receptor clusters may become uncoupled during remodeling. While coupled calcium release sites appear to show a normal spark frequency, subcellular spark behaviors are altered during T-tubule remodeling.
Fredrik Swift (Oslo) described recent studies about remodeling of the intracellular calcium stores, the sarcoplasmic reticulum (SR), and T-tubules following conditional knockout of the main SR calcium pump SERCA2. Cellular microscopy data from the SERCA2 knockout mouse showed changes of T-tubules. The SERCA calcium pump is responsible for SR re-uptake of 70-80% of intracellular calcium in mouse cardiac myocytes, and is downregulated in heart failure samples from patients. Using an inducible Cre-recombinase knockout strategy, relative protein abundance was downregulated to about 5% in the heart within few weeks, and the mice developed heart failure. Interestingly, the hearts did not develop hypertrophy or obvious myocyte loss, and survived for several weeks until spontaneous death. In electron microscopic sections the SR size (area) was significantly reduced, indicating a decreased calcium storage capacity, while the calsequestrin content and its organelle localisation were unchanged. Longitudinally oriented T-tubules appeared increased, and immunofluorescent staining for sodium/calcium exchangers and ryanodine receptors showed further remodeling. Furthermore, new dyadic release structures were suggested at the A-band region. The calcium transients and SR calcium content were decreased. Thus, in SERCA2 knockout hearts additional dyads may contribute to interactions between T-tubules and calcium release sites in heart failure.
Prof. Mark Anderson (Iowa) discussed T-tubule remodeling during the transition from hypertrophy to heart failure. Calcium release in cardiac myocytes was investigated in a rat model with hypertension induced heart failure. However, is T-tubule remodelling a common alteration in cardiomyopathy of different etiologies? In a different, pressure-overload rat model with a variety of ejection fraction outcomes (hypertrophy to severe heart failure) in situ confocal microscopy of T-tubules was performed. The degree of T-tubule remodeling following pressure overload correlated with the ejection fraction, and there was a delayed onset of remodeling in the right ventricle. In myocardial infarction, metoprolol treatment inhibited T-tubule remodeling in a post-MI mouse model. In summary, T-tubule remodeling may represent a common pathology in different heart failure models, and junctophilin loss was discussed as a potential molecular mechanism of uncoupling of ryanodine receptors from calcium release sites.
Dr. Michael Ibrahim (London) explained recent models and interventions which reverse the loss of T-tubules during mechanical unloading. Coming from observations in human heart failure with left ventricular assist devices (LVAD) he explained how heart failure might be related to loss of myocardial function, cell number, and to T-tubule remodeling. Mechanical unloading by LVAD led to clinical recovery in some patients, and this was correlated with normalization of action potentials and calcium transients in isolated cardiomyocytes. However, prolonged mechanical unloading can lead to muscle atrophy and T-tubule changes by itself, suggesting an important role of physiological mechanical load and concomitant T-tubule organization. Furthermore, prolonged unloading of failing hearts restored the prolonged calcium transient decay and and also calcium spark frequency. Hypertrophic phenotypes were dependent on the duration of load variation in different intervention models, and correlated with increased cell size and remodelling of the calcium transient. The protein T-cap was investigated as potential mechanism which may link certain potassium channels in T-tubules with calcium release sites. A T-cap knockout mouse showed progressive calcium transient defects with an increased variability of calcium release and increased spark frequency. Furthermore, ion conductance scanning microscopy showed a profound loss of T-tubule surface expression. In summary, the mouse model recapitulated some of the T-tubule changes seen in human cells, and calcium release could be modulated through different load paradigms.
Destroying and restoring cardiomyocyte architecture
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