Cardiotoxicity is a serious adverse effect of chemotherapy that encompasses a spectrum of disorders, ranging from relatively benign arrhythmias to potentially lethal conditions such as myocardial ischemia/infarction and cardiomyopathy. The toxicity of chemotherapeutic drugs can cause loss of myocytes' sarcolemmal integrity, release of bioactive markers into the extracellular environment (tissue and circulation) and ultimately leading to the necrosis of myocytes. The extent and severity of the necrosis can be monitored by the levels of bioactive markers.Therefore current research is aimed at finding biochemical markers with absolute cardiac specificity, high sensitivity and predictive value that can be used in early detection of patients with treatment-induced myocardial damage. Routinely used biomarkers like CK, CK-MB, and myoglobin do not meet the stated criteria. Their role in early diagnosis of chemotherapy-induced myocardial toxicity is controversial and limited.However, cardiac troponins, new nonconventional markers, have shown promising results in assessment and monitoring of both, early and late, clinical and subclinical damage to myocardium after chemotherapy.The article reviews clinical studies evaluating the role of cardiac troponins in the diagnosis of cardiotoxicity and their use in the management of cancer survivors.

Fractionated heart activation can be detected as late potentials from surface recordings of signal-averaged electrocardiograms (SA ECG) which are considered as a marker of sustained ventricular tachycardia. For animal studies, reference values in time and frequency domain analyses are essentially missing. In the present study, we have established reference values in SA ECG time domain analysis and time-frequency representation of heart activation in healthy dogs. A group of 25 healthy mongrel dogs (body weight 12-15 kg) was investigated. Wigner distribution and our modification of Fast Fourier transform (FFT), gliding window FFT, was applied in SA ECG frequency domain analysis. Reference values in time domain SA ECG were established. Time and voltage criteria were adapted to short duration of heart cycle and fast voltage decrement of the QRS complex in dogs. Wigner distribution and gliding window FFT were applied in order to describe mean heart activation in the frequency domain. Contribution of higher frequencies (30-80 Hz) was detected by both frequency analysis methods in the second third of ventricular activation in healthy animals. Presented results could offer a basis for further experimental arrhythmologic studies.

BACKGROUND:Endothelin-1 is a strong vasoconstrictor, high doses of which can cause prolonged vasoconstriction.MAIN PURPOSE:The aim of our study was to investigate as to whether the endothelin-induced vasoconstriction causes irreversible morphological changes in the myocardium in experimental animals and to verify the applicability of this experimental model in the study of the impact of endothelin.METHODS:Fourteen anaesthetized dogs were administered with 400 pmol of endothelin. The substance was applied into the left anterior descending coronary artery. The serum activities of AST, CK and LD enzymes, and changes in electric activity of the myocardium were monitored. The heart of one of the dogs was analyzed morphologically.RESULTS:Following the application of endothelin, vasoconstriction supervened, lasting from 25 to 27 minutes. Five dogs developed fibrillation of ventricles and died. The dogs which survived yielded changes in the activities of the investigated enzymes and changes in electric activity which were typical of focal impairment of the myocardium in sense of necrosis. Morphologically the changes represented disseminated fibrosis or minor scars in the myocardium.CONCLUSIONS:Application of endothelin into the coronary artery can cause irreversible structural changes in the myocardium. (Fig. 1, Ref. 18.).

OBJECTIVE:Large prospective studies in dogs with healed myocardial infarction (MI) recently show a positive relation between heart rate variability (HRV) and sudden cardiac death.METHODS:We have done similar experiments in dogs and we studied HRV, ECG and body surface potential maps (BSPM) in 26 normal mongrel dogs (10-15 kg) and 12 dogs with an experimental MI (ligation of LAD). A two-channel 8 hours lasting ECG recording was performed in all conscious dogs. The 2nd recording was done in Penthobarbital anaesthesia (30 mg/kg).RESULTS:We have found sinus arrhythmia (SA) in all 26 conscious dogs. The anaesthesia suppressed the sinus arrhythmia and HRV via compensatory tachycardia and alterations in baroreflexes. The suppression of arrhythmia was also present in dogs with myocardial infarction.CONCLUSIONS:It is suggested, that HRV and SA in dogs depend on conscious state and anaesthesia. On the basis of our results we can anticipate that the most important for HRV is the present status of the sympathetic nerve. We suggest, that our results are an important finding for experimental arrhythmology. (Fig. 4, Ref. 24.)

In the course of adaptation of the rabbit heart to volume load passive diastolic properties of the hypertrophic ventricle and myocardium were changing significantly. On day 30 following perforation of the aortic valve stiffness of the ventricle was reduced, yet normalized ventricular stiffness and myocardial stiffness were increased. These changes were prevented by beta adrenergic blockade during development of adaptation of the heart to volume load. Although ventricular stiffness was reduced, normalized ventricular stiffness and myocardial stiffness remained at the level of control values. The demonstrated effect of beta adrenergic blockade on passive diastolic properties of the ventricle and myocardium may be of value in preventing heart failure due to chronic hemodynamic load. (Tab.3,Ref.15.).

Adaptation of the rabbit heart to volume load of the left ventricle is characterized by hypertrophic growth. This process involves an increase in the mass and changes in the composition of the myocardium. In the fifth week after perforation of the aortic valve an increase in phospholipid content and in mitochondria and a decrease in protein content was observed in the myocardium. These changes precondition a transient hyperfunction of the cardiomyocytes, but they presumably lead also to the eventual loss of contractile capacity. When the hypertrophic process occurs under conditions of nonspecific beta-adrenergic blockade, the required increase in left ventricular mass is achieved yet the content of phospholipids, proteins and mitochondria remains unchanged. Long-term blockade of beta-adrenergic receptors may be one of the modes of affecting the expression of cardiac genes in such a way that the hypertrophic myocardium does not develop conditions resulting in heart failure.

Induced insufficiency of the aortal valve in rabbits is followed by gradual adaptation of the heart to volume load. In the period of developing hypertrophy, we studied the changes in the passive diastolic properties of the ventricle. By analyzing the passive relationship between the volume of the ventricular cavity and the intraventricular pressure, the stiffness of the ventricle, normalized ventricular stiffness, and myocardial stiffness were determined. On day 30 after inducing the volume verload, the stiffness constant of the ventricle was statistically significantly reduced, whereas the constant of normalized ventricular stiffness and the constant of myocardial stiffness were statistically significantly increased. The increased stiffness of the myocardium, which characterizes the volume verloaded, left ventricle in the period of developing hypertrophy, may represent one of the changes causing reversal of the adaptive response of the heart to hemodynamic verload after a certain period of time, gradually resulting in the development of the syndrome of heart failure.

After inducing haemodynamic cardiac overload in rabbits, the authors studied in several stages (1-14 months) the calcium transport activity of the mitochondrial and sarcoplasmic myocardial fractions using labelled 45CaCl2. A coincidence was found between changes in myocardial contractility and changes in calcium transport activity of intracellular organelles. A possible important role of mitochondria in this adaptive process was also documented. Since the calcium transport capacity of the sarcoplasmic reticulum progressively decreases (with the exception of the earliest stages following overload induction), it seems that increased myocardial contractility ensures enhanced Ca transport activity of the mitochondria. Myocardial contractility drops only at the time when the Ca transport activity of the mitochondria decreases. Since these changes occur already at the time of regression of myocardial hypertrophy, which precedes heart failure, it can be assumed that they are causally connected with the reduced contractility of a failing heart.

Respiratory and oxidative phosphorylation activity of mitochondria was studied in the course of the adaptation of the heart to haemodynamic overload in rabbit due to aortic valve insufficiency. In the period of developing cardiac hypertrophy, the rate of oxygen consumption in stage 3, i.e. in the stage of ATP formation, and the phosphorylation rate significantly increase. In the period of regression of cardiac hypertrophy, which precedes heart failure, the respiratory and oxidative phosphorylation activity does not significantly change. In a failing heart, the respiratory rate in stage 3 returns to normal and the phosphorylation rate increases in comparison with normal rabbits. The results of the study show that in the myocardium of hypertrophied non-failing as well as failing heart after prolonged haemodynamic overload, the primary function of mitochondria, i.e. energy production is sufficiently preserved.