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OUR MISSION: TO REDUCE THE BURDEN OF CARDIOVASCULAR DISEASE
Dr. Sylvain Richard
Better understanding of the intercellular connections between cardiomyocytes and ‘cardiofibroblasts’ was in the primary focus of this session.
Intracellular signalling following myocardial stretch Pr. B. Pieske (Graz, AT) showed that stretch induces both immediate and delayed inotropic effects in cardiomyocytes from the failing human myocardium. The initial phase is attributed to increased myofilaments Ca2+ sensitivity (Frank-Starling mechanism). The delayed inotropic response involves a SR-Ca2+-dependent slow force response (SFR) (Lewinski et al., 2004, Circulation Research, 94:1392). The SFR partly depends on activation of NHE1, resulting in increased intracellular Na+ and Ca2+ due to reverse-mode NCX activation. It was independent of autocrine/paracrine actions of Ang-II and ET-1 in the ventricular tissue. Besides Ca2+ dependent mechanisms (involving p44/42 MAP kinase and p90rsk activation), increased myofilament Ca2+ sensitivity through MLCK-induced phosphorylation of MLC2 was also found in both the atrium and the ventricle (Kockskämper et al., Prog Biophys Mol Biol. 2008;97:250-67). Acute Stretch Effects Pr. G. Iribe (Okayama, JP) presented new insights into acute stretch effects on cardiac Ca2+ handling. He showed that if electrical stimulation promotes Ca2+ mobilization from the sarcoplasmic reticulum (SR) to trigger cardiac contraction, mechanical stimulation can in turn regulate Ca2+ handling. He showed the effects of diastolic length changes achieved using computer-controlled carbon fibers attached to the two ends of guinea-pig cardiomyocytes loaded with Fura-2 AM, an indicator of intracellular free Ca2+. Intracellular Ca2+ transients and sarcomere length were measured simultaneously, and comparisons between stretched and non-stretched cells were made (Iribe & Kohl, 2008, Prog. Biophys. Mol. Biol., 97: 298-311). Caffeine application was used to assess SR Ca2+ content and Na+/Ca2+ free conditions to exclude other sources for Ca2+ movements. The main results show that diastolic stretch transiently enhances both the rate of SR Ca2+ rest-decay and post-depletion reloading of Ca2+ in the SR. These experimental findings along with mathematical simulation are consistent, at least in part, with the involvement of stretch-induced Ca2+ leak through the ryanodine receptors of the SR in combination with mechanically increased transarcolemmal Ca2+-influx.
Cardiac Fibroblasts Prof G.L. Smith (Glasgow, GB) discussed the role of cardiac fibroblasts from sino-atrial node function to infarct conduction. He first showed the functional consequences of a large transmural apical infarct on the epicardial activity in a rabbit model of chronic myocardial infarction (hearts isolated 8 weeks after coronary artery ligation). Optical mapping of membrane potential of the epicardial surface of the left ventricle, including the infarcted zone, in response to endocardial and epicardial pacing was performed using the voltage-sensitive dye RH237 (Walker et al., J. Cardiovasc. Electrophysiology, 2007, 18: 862-868). The main results showed that the infarcted zone in the mid-wall and epicardium support normal activation. In contrast, an area of slow conduction emerges at the peri-infarct zone on epicardial stimulation. Then, Prof. Smith discussed the nature and role of intercellular coupling between cardiomyocytes and cardiac fibroblasts forming intercellular junctions after 24 h in co-culture. He then showed clear evidence that field stimulation of the cardiomyocytes modulates intracellular Ca2+ responses in the connected fibroblasts in primary co-cultures, whereas no major effect occurred on the action potential waveform (Chilton et al., 2007,J. Physiol, 583.1:225-236). However, application of the hormone sphingosine-1-phosphate, which had no direct effect on the cardiomyocytes, induced a dramatic depolarization of these cells (-20 mV) when connected to fibroblasts. The induction of a quasi-linear conductance in the fibroblasts was involved, thereby causing the depolarization of cardiomyocytes and loss of excitability. Magnetic resonance imaging-based three-dimensional heart modelling Dr. G. Plank (Graz, AT) presented an overview of the current efforts of a consortium involving several universities (Oxford, Graz, Johns Hopkins) to achieve the construction of realistic histoanatomical heart models with near cellular resolution. He showed that magnetic resonance imaging-based three-dimensional approach can be more predictive than in the past with improved structural representation of the tissues, providing information on fibers, layer organization, etc. Dr. Plank anticipated that near real time simulation will be feasible with small mammalian hearts (up to a rabbit) within the next two years.
In conclusion, this session nicely illustrated how stretch can modulate the contraction of cardiomyocytes in both Ca2+-independent and Ca2+-dependent manners. Mechanical environment regulates Ca2+ cycling, especially during the diastolic pre-load of the heart, in addition to the well-known Frank-Starling effects. The functional connection between cardiomyocytes and fibroblasts with an effect on Ca2+ signaling may have an impact on autocrine/paracrine functions or collagen formation with high relevance for physiopathology. Finally, integrating functional (in addition to ultrastructural) information such as the effects of stretch on cell-to-cell interaction and cardiomyocyte contraction will be essential for the development of predictive useful ‘in silico’ models to study the physiopathology of the beating heart.
Structure/function relationships in the heart
This congress report accompanies a presentation given at the ESC Congress 2008. Written by the author himself/herself, this report does not necessarily reflect the opinion of the European Society of Cardiology.
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