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Research interest

Cardiac diseases: arrhythmias and heart failure

Cardiac diseases are among the leading causes of death worldwide. Ca²⁺ is a key player in both physiological and pathological processes in the heart. During normal excitation-contraction coupling, Ca²⁺ enters the cardiac myocyte during an action potential through voltage-dependent L-type Ca²⁺ channels in the sarcolemma. This Ca²⁺ entry triggers a huge release of Ca²⁺ from the sarcoplasmic reticulum via ryanodine receptor (RyR) Ca²⁺ release channels, a process termed Ca²⁺-induced Ca²⁺ release. Ultimately, this increase in cytoplasmic Ca²⁺ causes Ca²⁺ binding to the myofilaments and activation of contraction. The strength of contraction is regulated by the amount of Ca²⁺ released from the SR. Increased SR Ca²⁺ release causes augmented contraction, whereas decreased SR Ca²⁺ release results in reduced contraction of the cardiomyocyte. Disturbances of this highly regulated process may lead to cardiac disease including arrhythmias and heart failure, which are among the most serious and widespread cardiac diseases. A number of cardioactive peptides is involved in the regulation of cardiac Ca²⁺ homeostasis and may either aggravate or improve cardiomyocyte function in cardiac disease.

The research interest of our group is focused on the following topics:

1) Cytoplasmic Ca²⁺ signaling and arrhythmias

Systolic SR Ca²⁺ release is essential for contraction of the myocyte. Diastolic SR Ca²⁺ release, on the other hand, is detrimental. It activates the sarcolemmal electrogenic Na⁺/Ca²⁺ exchanger resulting in depolarization of the resting membrane potential (delayed afterdepolarizations), which in turn may trigger arrhythmias. In the normal heart, diastolic SR Ca²⁺ release is a rare event. In the stressed or diseased heart, however, diastolic SR Ca²⁺ release may increase and thus enhance the propensity for arrhythmias. Increased diastolic SR Ca²⁺ release has been found in atrial myocytes from patients with atrial fibrillation, the most common cardiac arrhythmia, as well as in ventricular myocytes in heart failure, where it is thought to trigger the fatal arrhythmias associated with the disease. Pharmacological agents normalizing aberrant diastolic SR Ca²⁺ release in cardiac diseases associated with arrhythmias are currently being tested for their potential use as novel anti-arrhythmic drugs.

2) Nucleoplasmic Ca²⁺ signaling and excitation-transcription coupling

Nucleoplasmic Ca²⁺ regulation in cardiac myocytes has gained much less attention than cytoplasmic Ca²⁺ regulation. Recent evidence, however, indicates that localized nucleoplasmic Ca²⁺ increases may specifically alter transcription via Ca²⁺-dependent enzymes (e.g. nuclear Ca²⁺/calmodulin-dependent protein kinase II). The link between electrical and/or pharmacological stimulation of the cardiac myocyte, nucleoplasmic Ca²⁺, and transcription is termed excitation-transcription coupling. Altered excitation-transcription coupling may be involved in the remodeling processes occurring during initiation and progression of cardiac diseases, including atrial fibrillation and heart failure. A better understanding of nucleoplasmic Ca²⁺ regulation thus holds the promise for the development of novel treatment strategies against cardiac diseases associated with remodeling.

3) Cardioactive peptides: angiotensin II, endothelin-1, and urocortin II

Cardioactive peptides are involved in a variety of physiological and pathophysiological processes including arrhythmogenesis and the development and progression of hypertrophy and heart failure. They are major drug targets in cardiovascular disease. Inhibition of the angiotensin system by either ACE inhibitors or AT1 receptor blockers is used for the treatment of hypertension and heart failure, whereas the endothelin receptor blocker bosentan is used for the treatment of pulmonary hypertension.

Urocortins (including urocortin II) represent a family of peptides involved in cardiovascular homeostasis. They exert pronounced effects on cardiac myocytes as well as on coronary and peripheral vessels. Although beneficial in animal models of heart failure, the cellular actions of urocortins on cardiac myocytes are only incompletely understood. A better understanding of the specific actions of urocortins on cardiac myocytes in health and disease, however, is a pre-requisite for their potential therapeutic use in heart failure.