The multifunctional role of calcium in the heart: a tempting target

The sole purpose of the heart is to pump blood through the body. In order to achieve this, it is important that the rhythm is regular and controlled, that the contractile force of the muscle is sufficient, and that the macrostructure of the heart retains the right balance, between for example wall thickness and volume of the lumen. Remarkably, calcium plays an important role in all these processes. This multifaceted role of calcium in the heart is mirrored in what happens in pathology. Disturbances in calcium balance can lead to disruption of the cardiac rhythm (arrhythmias), it can lead to reduced contraction or insufficient relaxation, and it can induce unbalanced, pathological hypertrophy. Because, of this, calcium is a tempting target. But, as it is involved in multiple facets of cardiac function, it will also be difficult to influence one calcium-dependent factor, without influencing other calcium-sensitive processes as a side effect. In this thesis, we nonetheless tried to target cardiac calcium while preventing negative secondary effects. In the preface of this thesis the rationale behind this research is laid out, while in the following chapter physiological excitation-contraction and impulse propagation is described, as well as an overview of arrhythmogenic mechanisms, with an emphasis on triggered activity. Chapter 3 gives an in depth insight into physiological ventricular remodeling, especially focused on the chronic atrioventricular block dog. This model is used in the following chapter to research the effects of the calcium-dependent protein CaMKII in long-QT dependent arrhythmias and compensated hypertrophy. It turned out that CaMKII was more activated in compensated hypertrophy, but not more expressed. Nonetheless, acute inhibition proved to be an effective anti-arrhythmic strategy. In chapter 5 we used a mouse model with chronic CaMKII inhibition and decompensated hypertrophy accompanied by reduced conduction velocity and arrhythmias. Although chronic inhibition did not prevent arrhythmias, inhibition was able to rescue conduction velocity. In the subsequent chapter another mouse model with decompensated hypertrophy and arrhyhmias was used as the research tool, namely mice with overexpression of calcineurin, another calcium-sensitive signalling protein. In this case chronic CaMKII inhibition was ineffective in rescuing conduction velocity related parameters like connexin and sodium channel expression. The thesis takes a different route in chapter 7, where it is described what the problem is with verapamil and other calcium blockers: a negative side effect of reduced cardiac contractility. We believed we could circumvent this side effect by using a combined blocker of the LTCC and NCX, as described in chapter 8. This indeed seemed to be the case. Compared to verapamil it was just as anti-arrhythmic, but with negligible effects on left ventricular pressure. Chapter 9 comprises the general discussion, which tries to resolve a number of confusing findings, and gives a general appraisal of the combined data of the thesis. Conclusion The original hypothesis was partially confirmed. It was indeed possible to acutely inhibit cardiac arrhythmias by targeting calcium without reduced cardiac contraction. However, chronic modulation of calcium-sensitive signalling pathways to prevent pathological cardiac remodelling turned out not to be so straightforward. In all, it must be concluded that the acute effects of calcium in excitation and contraction are sufficiently known to warrant optimism in the near term, but that the chronic effects of calcium-dependent signalling will need further elucidation before reliable predictions can be made on the effects of targeting these pathways