[Mechanisms of cardiotoxicity of oncological therapies]. / Mechanismen der Kardiotoxizität onkologischer Therapien.

BACKGROUND: Oncological therapies show a number of undesired adverse effects on the cardiovascular system. In particular, the side effects of recently established oncological therapies are incompletely understood and clinical data are lacking in the interpretation of novel cardiac complications. OBJECTIVE: This article provides a short overview of the mechanisms of cardiac side effects of certain oncological therapies. MATERIAL AND METHODS: The review is mainly based on data from preclinical studies. RESULTS: Numerous toxic side effects have already been described and investigated in preclinical models. For certain groups of drugs (e.g. anthracyclines, tyrosine kinase inhibitors and immune checkpoint inhibitors) the underlying molecular mechanisms are still not fully understood. CONCLUSION: An improved understanding of the molecular mechanism involved in cardiotoxicity might help improve the quality of clinical decisions. Additionally, it will provide new insights into the pathophysiology of cardiac diseases. The aim is to use the results of translational research and to clinically implement them in suitable cardio-oncology units.

Establishing an oncocardiology service.

Oncocardiology is an emerging field in cardiovascular healthcare. Besides establishing surveillance and follow-up strategies for cancer patients, it will be essential to set up specialized oncocardiology services. However, there is a lack of clinical studies to give evidence-based recommendations regarding cardiological diagnostic and therapeutic approaches for cancer patients. An oncocardiology service is a patient-centered structure that aims to integrate research and interdisciplinary patient care to bridge this gap. We discuss the current challenges in developing an oncocardiology service and review the literature on this topic. We further provide an overview of the essential diagnostic tools and upcoming ethical issues to be considered in the management of oncology patients.

Acylation of proteins by myristic acid in isolated mitochondria.

Isolated and highly purified mitochondria from rat liver were incubated with [1-14C]myristate, solubilized in boiling sodium dodecyl sulfate, and analyzed by polyacrylamide gel electrophoresis and autoradiography. Six to eight protein bands were found to be radioactively labeled. If the mitochondria were heated for 5 min at 95 degrees C prior to incubation with this fatty acid, no labeling was observed. By preexposing the mitochondria to unlabeled fatty acids of varying chain lengths, the extent of labeling by [1-14C]myristate was reduced in a chain length-dependent manner, exhibiting maximal inhibition at lauric acid. Reversibility of the labeling was demonstrated by chasing the incorporated radioactivity with unlabeled fatty acids of varying chain length, resulting in a maximal displacement of the tracer again by lauric acid. Fractionation of the labeled mitochondria into mitochondrial matrix and inner mitochondrial membrane components before or after labeling showed that the modified proteins are located inside the inner mitochondrial membrane. In both cases, the pattern of labeling was different from the one observed with intact mitochondria. The labeled bands in the gel were sensitive to alkaline methanol or hydroxylamine treatment. The radioactivity recovered after this treatment co-migrated with myristic acid on thin layer chromatography plates. The chain length specificity and the rapid reversibility of the observed acylation argue for a new type of reaction, different from the acylation observed in whole cells. The possible involvement of the acylated proteins in the regulation of oxidative phosphorylation is discussed.

Transient kinetics of thermodynamic buffering.

The transient response of mitochondrial ATP production towards perturbations was studied by analyzing the trajectories leading from arbitrary initial conditions of the adenine nucleotide pool to the final steady state. These trajectories were calculated from differential equations based on linear relations between flows and thermodynamic forces of the adenylate kinase system including oxidative phosphorylation. The motion of the system along the trajectories consists of two phases: (1) a rapid phase leading from initial states to a common relaxation curve; and (2) a slow phase leading along the relaxation curve to the final steady state. The first phase corresponds to a motion close to the loci of constant adenylic energy charge. In line with this observation is the finding that the energy charge is a constant of motion of the adenylate kinase reaction. The second phase corresponds to a motion along a relaxation curve characterized by minimal Lyapunov exponents in the concentration space of the adenine nucleotides. Thus, both phases of the transient kinetics can be approximated in terms of thermodynamic functions to a high degree of precision. Incubations with isolated rat liver mitochondria were in excellent agreement with the theoretical predictions. In summary, these studies show that the adenylate kinase system not only optimizes the efficiency of oxidative phosphorylation through thermodynamic buffering but, in addition, also deeply influences the transient response of the whole system.