Using biomarkers and early prophylactic treatment to prevent cardiotoxicity in cancer patients on chemotherapy

Cardiac toxicity induced by anticancer therapy is of considerable concern for, once it develops, it may compromise the clinical effectiveness of treatment independent of the oncologic prognosis. The main strategy to minimize cardiotoxicity is to detect high-risk patients and begin prophylactic treatment as early as possible. According to the current standard for monitoring cardiac function cardiotoxicity is usually detected only once a functional impairment has already occurred, thus precluding any chance of prevention. The measurement of cardio-specifi c biomarkers can be a valid diagnostic tool for the early identifi cation, assessment and monitoring of cardiotoxicity. The role of Troponin I in identifying patients with subclinicalcardiotoxicity and their subsequent treatment with angiotensin- converting enzyme inhibitors to prevent left ventricular ejection fraction (LVEF) reduction and cardiac events, is emerging as an effective strategy against these complications. When this approach is not feasible, a complete LVEFrecovery and a reduction in cardiac events may be achieved if left ventricular dysfunction (LVD) is detected early and the patient promptly treated with angiotensin-converting enzyme inhibitors, possibly in combination with beta-blocking agents

Early detection of doxorubicin-induced cardiotoxicity and its prevention by carvedilol

Background: The objective was to detect doxorubicin (Dox) - induced myocardial injury at early stage by quantitative estimation of cardio specific protein, cardiac troponin I (cTnI) and to explore the cardioprotective effects of carvedilol.Methods: The study design was lab-based randomized controlled in-vivo in rabbits conducted from January to August 2012. Cardiotoxicity was produced by single intravenous injection of 12 mg/kg body weight (BW) of Dox in a group of rabbits, control group was treated with normal saline only and the rabbits of third group were pre-treated with carvedilol 30 mg/kg of BW for 10 days before injecting Dox.Results: Dox induced cardiotoxicity was depicted by markedly raised serum levels of cTnI, creatine kinase-MB, lactate dehydrogenase, and Grade 3 necrosis of the heart tissue in rabbits. The pre-treatment with carvedilol resulted in improved serum levels of these biomarkers and the histological picture of heart tissue.Conclusions: Quantitative serum estimation of cTnI detects the presence of cardiotoxicity much before cardiac dysfunctions can be revealed by any other diagnostic technique. It can lead to significant economic impact in the management of cancer patients because the troponin-negative subjects can be excluded from long-term cardiac monitoring programs that involve high costs imaging techniques. The outcome of Dox chemotherapy can be made successful with the concurrent use of carvedilol

Diagnosis, Investigation and Management of Patients with Acute and Chronic Myocardial Injury

The application of high-sensitivity cardiac troponins in clinical practice has led to an increase in the recognition of elevated concentrations in patients without myocardial ischaemia. The Fourth Universal Definition of Myocardial Infarction encourages clinicians to classify such patients as having an acute or chronic myocardial injury based on the presence or absence of a rise or a fall in cardiac troponin concentrations. Both conditions may be caused by a variety of cardiac and non-cardiac conditions, and evidence suggests that clinical outcomes are worse than patients with myocardial infarction due to atherosclerotic plaque rupture, with as few as one-third of patients alive at 5 years. Major adverse cardiovascular events are comparable between populations, and up to three-fold higher than healthy individuals. Despite this, no evidence-based strategies exist to guide clinicians in the investigation of non-ischaemic myocardial injury. This review explores the aetiology of myocardial injury and proposes a simple framework to guide clinicians in early assessment to identify those who may benefit from further investigation and treatment for those with cardiovascular disease

THE CARDIOTOXICITY OF CARBON MONOXIDE

The mechanism(s) responsible for the cardiotoxicity of CO are not clear and do not appear to arise solely from tissue hypoxia. Tissue hypoxia is produced by CO binding to haemoglobin and reducing the amount of oxygen carried by the blood in vivo. CO-induced hypoxia in vivo may be responsible for producing conditions such as those found during ischaemia/reperfusion (l/R) injury. Reactive oxygen species (ROS) produced during l/R injury is established and responsible for cellular/tissue damage from the oxidative damage. We postulate that oxidative stress is responsible for the CO-associated cardiac morbidities found in some cases following severe acute exposure to CO. Isolated perfused rat hearts were used to investigate the physiological and biochemical changes in hearts following CO exposure. Hearts were perfused with buffer equilibrated with different mixtures of CO (0-0.05% CO for 30 minutes) in the presence of 21% oxygen during and after CO exposure (for 90 minutes), i.e. normoxic conditions were used throughout. Some hearts were perfused with water-soluble antioxidants (ascorbic acid and TroloxC) before and during the CO exposure. The reduced heart rate and perfusate flow suggest that CO may have a direct effect in heart tissue. Biochemical measurements suggest that no tissue hypoxia occurred under these conditions. The results provide evidence to suggest that oxidative stress occurred in ventricle tissue after CO exposure and was attenuated by the antioxidants. However, isolated rat liver mitochondria exposed to CO and/or hyperoxia showed no ROS production suggesting that mitochondria may not be a source of the oxidative stress. CO exposure may also produce altered myocardial energetics by oxidatively modifying and/or binding to myoglobin. Tissue damage initiated by CO-induced oxidative stress and hypoxia may potentiate ageing within heart tissue in vivo and could be responsible for producing the observed CO-associated heart morbidity in an MR-like injury

Doxorubicin-Induced Oxidative Injury of Cardiomyocytes - Do We Have Right Strategies for Prevention?

Anthracyclines are among the most utilised antitumour drugs ever developed. The discovery of one of the leading compounds, doxorubicin (DOX) in early 1960s was a major advance in the fight against cancer. According to the WHO, it belongs to the group of 17 essential drugs that are used to treat curable cancers or cancers for which the cost-benefit ratio clearly favours drug treatment (Sikora et al., 1999). It is used, often with other antineoplastic, in the treatment of Hodgkin's disease, non-Hodgkin's lymphomas, acute leukaemias, bone and soft-tissue sarcoma, neuroblastoma, Wilm's tumour, and malignant neoplasms of the bladder, breast, lung, ovary, and stomach. The mechanisms of cytotoxicity of DOX in cancer cells is complex including: inhibition of both DNA replication and RNA transcription; free radicals generation, leading to DNA damage or lipid peroxidation; DNA cross-linking; DNA alkylation; direct membrane damage due to lipid oxidation and inhibition of topoisomerase II (Gewirtz, 1999; Minotti et al., 2004). Today, topoisomarase II is generally recognized to be the cellular target of DOX, which act by stabilizing a reaction intermediate in which DNA strands are cut and covalently linked to this enzyme (Simunek et al., 2009). It blocks subsequent DNA resealing. Failure to relax the supercoiled DNA blocks DNA replication and transcription. Furthermore, DNA strand breaks may trigger apoptosis of cancer cells. However, as with all traditional antineoplastic drugs, DOX administration is accompanied by adverse drug reactions arising from the limited selectivity of their anticancer action (Aronson et al., 2006; McEvoy et al., 2010). Particularly common are bone marrow depression, which may be dose-limiting. White cell count reaches a nadir 10 to 15 days after a dose and usually recovers by about 21 days. Gastrointestinal disturbances include moderate or sometimes severe nausea and vomiting; stomatitis and oesophagitis may progress to ulceration. Alopecia occurs in the majority of patients. Occasional hypersensitivity reactions may also occur. However, a cumulative-dose dependent cardiac toxicity has been a major limitation of DOX use

Nové chelátory železa a antioxidancia u modelu akutního infarktu myokardu a oxidačního stresu navozeného katecholaminy - vliv na základní biochemické parametry

I. SOUHRN ÚVOD: Železo je nezbytným prvkem pro celou řadu fyziologických procesů, mj. přenos kyslíku, syntézu DNA a tvorbu ATP. Osud železa v organismu je pečlivě regulován zejména na úrovni absorpce a distribuce pravděpodobně z důvodu neexistujícího specifického aktivního exkrečního mechanismu pro železo. Každé porušení homeostázy železa může vést k objevení se volného (nevázaného nebo slabě vázaného) železa, které je schopno katalyzovat tvorbu reaktivních forem kyslíku (ROS) prostřednictvím Haber-Weissova mechanismu. Kardiovaskulární onemocnění, zejména pak ischemická choroba srdeční (ICHS), zůstávají přes recentní vědecké pokroky vážným medicinálním problémem. Nejzávažnější formou ICHS je akutní infarkt myokardu (AIM). Jeho patofyziologie zahrnuje ve většině případů iniciální ischemickou periodu v důsledku poruchy koronárního krevního proudu způsobeného trombózou nasedající obvykle na ateroskleroticky postiženou koronární tepnu. Ischémie podstatně mění tkáňovou homeostázu s následným objevením se volného cytosolického železa. Obnova koronárního krevního průtoku (tzv. reperfúze) je jedinou možností k záchraně poškozeného myokardu, je ale na druhé straně spojena s uvolněním zmíněného volného železa do cirkulace a tvorbou ROS jak uvnitř tak vně buňky. Chelátory železa představují rozsáhlou skupinu léčiv s...I. SUMMARY Background: Iron is an essential element necessary for many physiological processes involving oxygen transport, DNA-synthesis and ATP-formation. The fate of iron in the organism is tightly regulated especially at the absorption and distribution level probably mainly due to lack of specific active iron excretion mechanism. Any derangement of iron homeostatis may lead to appearance of free (unbound or loosely bound) iron, which can catalyse reactive oxygen species (ROS) production by Haber-Weiss chemistry. Cardiovascular diseases, particularly coronary heart disease (CHD), remain notwithstanding recent scientific advances important therapeutic problem. The most serious form of CHD represents acute myocardial infarction (AMI). The pathophysiology of AMI involves in most cases initial ischaemic period caused by coronary blood flow derangement due to a thrombus formation. Ischaemia alters substantially tissue homeostasis with subsequent cytosolic free iron appearance. Reconstitution of coronary blood flow (reperfusion) represents the only way for myocardial tissue recovery although on the other hand, it is linked with a release of free redox-active iron in the circulation and formation of ROS both intracellularly as well extracellularly. Iron chelators are a large group of drugs with very...Katedra farmakologie a toxikologieDepartment of Pharmacology and ToxicologyFaculty of Pharmacy in Hradec KrálovéFarmaceutická fakulta v Hradci Králov