Diagnosis of myocardial infarction (MI) is based on ST-segment elevation on electrocardiographic evaluation and/or elevated plasma cardiac troponin (cTn) levels. However, troponins lack the sensitivity required to detect the onset of MI at its earliest stages. Therefore, to confirm its viability as an ultra-early biomarker of MI, this study investigates the release kinetics of cardiac myosin binding protein-C (cMyBP-C) in a porcine model of MI and in two human cohorts. Release kinetics of cMyBP-C were determined in a porcine model of MI (n = 6, pigs, either sex) by measuring plasma cMyBP-C level serially from 30 min to 14 days after coronary occlusion, with use of a custom-made immunoassay. cMyBP-C plasma levels were increased from baseline (76 ± 68 ng/l) at 3 h (767 ± 211 ng/l) and peaked at 6 h (2,418 ± 780 ng/l) after coronary ligation. Plasma cTnI, cTnT, and myosin light chain-3 levels were all increased 6 h after ligation. In a cohort of patients (n = 12) with hypertrophic obstructive cardiomyopathy undergoing transcoronary ablation of septal hypertrophy, cMyBP-C was significantly increased from baseline (49 ± 23 ng/l) in a time-dependent manner, peaking at 4 h (560 ± 273 ng/l). In a cohort of patients with non-ST segment elevation MI (n = 176) from the SYNERGY trial, cMyBP-C serum levels were significantly higher (7,615 ± 4,514 ng/l) than those in a control cohort (416 ± 104 ng/l; n = 153). cMyBP-C is released in the blood rapidly after cardiac damage and therefore has the potential to positively mark the onset of MI.
Key points• Abnormal oscillations of calcium (Ca 2+ ) concentration in cardiac Purkinje cells (P-cells) have been associated with life-threatening arrhythmias, but the mechanism by which these cells control their Ca 2+ level in normal conditions remains unknown.• We modelled our previous hypothesis that the principal intracellular Ca 2+ compartment (endoplasmic reticulum; ER) which governs intracellular Ca 2+ concentration, formed, in P-cells, three concentric and adjacent layers, each including a distinct Ca 2+ release channel. We then tested the model against typical Ca 2+ variations observed in stimulated P-cells.• We found in swine P-cells, as in the rabbit and dog, that stimulation evokes an elevation of Ca 2+ concentration first under the membrane , which then propagates to the interior of the cell.• Our mathematical model could reproduce accurately this typical 'centripetal' Ca 2+ spread, hence supporting (1) the existence of the '3 layered' Ca 2+ compartment, and (2) its central role in the regulation of Ca 2+ concentration in P-cells.• To model the 'centripetal' Ca 2+ spread, local variations of Ca 2+ concentration were calculated for a virtual cell environment encompassing three different regions that mimicked the three layers of ER in P-cells. Various tests of the model revealed that the second intermediate layer was essential for 'forwarding' the Ca 2+ elevation from the periphery to the cell centre.• This novel finding suggests that a thin intermediate layer of specific ER Ca 2+ channels controls the entire Ca 2+ signalling of P-cells. Because Ca 2+ plays a role in the electric properties of P-cells, any abnormality affecting this intermediate region is likely to be pro-arrhythmic and could explain the origin of serious cardiac arrhythmias known to start in the Purkinje fibres.Abstract Despite strong suspicion that abnormal Ca 2+ handling in Purkinje cells (P-cells) is implicated in life-threatening forms of ventricular tachycardias, the mechanism underlying the Ca 2+ cycling of these cells under normal conditions is still unclear. There is mounting evidence that P-cells have a unique Ca 2+ handling system. Notably complex spontaneous Ca 2+ activity was previously recorded in canine P-cells and was explained by a mechanistic hypothesis involving a triple layered system of Ca 2+ release channels. Here we examined the validity of this hypothesis for the electrically evoked Ca 2+ transient which was shown, in the dog and rabbit, to occur progressively from the periphery to the interior of the cell. To do so, the hypothesis was incorporated in a model of intracellular Ca 2+ dynamics which was then used to reproduce numerically the Ca 2+ activity of P-cells under stimulated conditions. The modelling was thus performed through a 2D computational array that encompassed three distinct Ca 2+ release nodes arranged, respectively,
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