Die vorliegende Studie zeigt erstmals, dass eine erhöhte Ca2+-Empfindlichkeit der kardialen Myofilamente im Tiermodell einen selbstständigen Risikofaktor bei der Entstehung von Herzrhythmusstörungen darstellt. Dies konnte sowohl für chronische Erhöhung der Ca2+-Empfindlichkeit im Rahmen einer Familiären Hypertrophen Kardiomyopathie (FHK) als auch für eine akute Erhöhung mit Hilfe eines Ca2+-Sensitizers gezeigt werden. Die Ergebnisse der Arbeit bieten so eine mögliche Erklärung für plötzlichen Herztod bei bestimmten Patienten mit FHK. Sie schränken weiterhin den Einsatz von Ca2+-Sensitizern ein. Schließlich beleuchten sie einen bisher kaum untersuchten Aspekt in der Arrhythmogenese von Herzinsuffizienz und nach einem Myokard-Infarkt. Auf zellulärer Ebene findet sich ein veränderter Ca2+-Zyklus mit erniedrigten und verlangsamten Transienten. Diese Veränderungen sind wahrscheinlich eine direkte Konsequenz der erhöhten Bindungsaffinität für Ca2+. Die Myofilamente sind „klebriger“ für Ca2+, während der Systole wird mehr Ca2+ gebunden, während der Diastole hingegen dissoziiert es langsamer. Bei adrenerger Stimulation und schnellen Herzfrequenzen mit entsprechender Verkürzung der Diastole kommt es zu erhöhtem diastolischem [Ca2+]i und zu erhöhten Ca2+-Inhalt des Sarkoplasmatischen Retikulums. Der so veränderte Ca2+-Zyklus führt wahrscheinlich mit Hilfe des Na+/Ca2+-Austauschers zu Veränderungen der Repolarisation des Aktionspotentials. Bei schnellen Herzfrequenzen treten Aktionspotential-Verlängerung, Ca2+-abhängige Nachdepolarisationen und getriggerte Schläge auf. Auf Organ-Ebene findet sich eine verkürzte Refraktärzeit. Damit sind sowohl ein Trigger als auch ein arrhythmogenes Substrat für die beobachteten ventrikulären Arrhythmien gegeben. / The present study shows for the first time that increased Ca2+-sensitity of the cardiac myofilaments is an indepent mechanism in the development of cardiac arrhythmias. This could be shown both for chronically increased Ca2+-sensitity in Familial Hypertrophic Cardiomyopathy (FHC) and for acute drug-induced Ca2+-sensitization. The results provide an explanation for sudden cardiac death in certain patients with FHC. Moreover they limit the use of Ca2+-sensitizers. Furthermore they elucidate new aspects in the arrhythmogenesis of important aquired hearts diseases such as heart failure and myocardial infarction. On the cellular level the Ca2+-cycle is altered, Ca2+-transients show a smaller amplitude and slower rate of decay. These changes are probably a direct consequence of the increased Ca2+-puffering capacity. The myofilaments are “sticky” for Ca2+, durig systole more Ca2+ is bound while the dissociation during diastole is decelerated. With adrenergic stimulation and faster frequencies there is an increased diastolic [Ca2+]i and subsequently an Ca2+-overloading of the Sarcoplasmatic Reticulum. These changes in the Ca2+-cycle cause remodelling of the action potential repolarisation via the Na+-Ca2+-exchanger. At fast frequencies one finds action potential prolongation, Ca2+-dependent afterdepolarisations and triggered activity. On the organ level Ca+-sensitized hearts show a shortened refractory period. Thus there is both trigger and substrate for the observed ventricular arrhytrhmia.

The monitoring of cognitive functions is central to the assessment and consecutive management of multiple sclerosis (MS). Though, especially cognitive processes that are central to everyday behavior like dual-tasking are often neglected. We examined dual-task performance using a psychological-refractory period (PRP) task in N = 21 patients and healthy controls and conducted standard neuropsychological tests. In dual-tasking, MS patients committed more erroneous responses when dual-tasking was difficult. In easier conditions, performance of MS patients did not differ to controls. Interestingly, the response times were generally not affected by the difficulty of the dual task, showing that the deficits observed do not reflect simple motor deficits or deficits in information processing speed but point out deficits in executive control functions and response selection in particular. Effect sizes were considerably large with d∼0.80 in mild affected patients and the achieved power was above 99%. There are cognitive control and dual tasking deficits in MS that are not attributable to simple motor speed deficits. Scaling of the difficulty of dual-tasking makes the test applied suitable for a wide variety of MS-patients and may complement neuropsychological assessments in clinical care and research setting.

The monitoring of cognitive functions is central to the assessment and consecutive management of multiple sclerosis (MS). Though, especially cognitive processes that are central to everyday behavior like dual-tasking are often neglected. We examined dual-task performance using a psychological-refractory period (PRP) task in N = 21 patients and healthy controls and conducted standard neuropsychological tests. In dual-tasking, MS patients committed more erroneous responses when dual-tasking was difficult. In easier conditions, performance of MS patients did not differ to controls. Interestingly, the response times were generally not affected by the difficulty of the dual task, showing that the deficits observed do not reflect simple motor deficits or deficits in information processing speed but point out deficits in executive control functions and response selection in particular. Effect sizes were considerably large with d∼0.80 in mild affected patients and the achieved power was above 99%. There are cognitive control and dual tasking deficits in MS that are not attributable to simple motor speed deficits. Scaling of the difficulty of dual-tasking makes the test applied suitable for a wide variety of MS-patients and may complement neuropsychological assessments in clinical care and research setting.