The acute cessation of blood supply to the cardiac musculature during infarction leads to irreversible tissue damage and necrosis. These days the most efficient therapy to save damages myocardium is the revascularization by either thrombolysis, percutaneous coronary intervention (PCI), or coronary bypass (CABG) surgery. However, the restoration of blood flow leads to further tissue injury. This phenomenon is termed ischemia/reperfusion injury, which can manifest in 4 ways: an increase in the amount of infarcted tissues (see Figure 1), more pronounced microvascular obstruction, increased probability of arrhythmias, decreased cardiac contractility.
Figure 1: A slice of rat heart undergone ischemia/reperfusion and stained with Evan’s blue and TTC. Pale area on the left slice represents infarcted tissue. The area of infarcted tissue is decreased by the application of a cardioprotective pharmacological agent.
Licensed pharmacological tool for the treatment of ischemia/reperfusion injury is not yet available despite the very intensive research in the field, however, there is a significant need for them to improve acute and long-term survival and/or quality of life of patients with infarction. Therefore, we study the molecular aspects of cardiac ischemia/reperfusion injury to identify novel pharmacological targets. Furthermore, we study the interaction between pharmacons used for other symptoms and the extent of ischemia/reperfusion injury (hidden cardiotoxicity of drugs), and the effect of metabolic diseases on cardioprotective interventions and treatments.
Effect of pharmacological agents on ischemia/reperfusion injury: the significance of hidden cardiotoxicity
Unexpected cardiac adverse effects are the leading causes of discontinuation of clinical trials and withdrawal of drugs from the market (see figure 2). Since the original observations in the mid-90s, it has been well established that cardiovascular risk factors and comorbidities (such as ageing, hyperlipidaemia, and diabetes) and their medications (e.g. nitrate tolerance, adenosine triphosphate-dependent potassium inhibitor antidiabetic drugs, statins, etc.) may interfere with cardiac ischaemic tolerance and endogenous cardioprotective signalling pathways. Indeed drugs may exert unwanted effects on the diseased and treated heart that is hidden in the healthy myocardium. Hidden cardiotoxic effects may be due to (i) drug-induced enhancement of deleterious signalling due to ischaemia/reperfusion injury and/or the presence of risk factors and/or (ii) inhibition of cardioprotective survival signalling pathways, both of which may lead to ischaemia-related cell death and/or pro-arrhythmic effects. This led to a novel concept of ‘hidden cardiotoxicity’, defined as cardiotoxity of a drug that manifests only in the diseased heart with e.g. ischaemia/reperfusion injury and/or in the presence of its major comorbidities. Little is known on the mechanism of hidden cardiotoxocity, moreover, hidden cardiotoxicity cannot be revealed by the routinely used non-clinical cardiac safety testing methods on healthy animals or tissues. Therefore, here, we emphasize the need for development of novel cardiac safety testing platform involving combined experimental models of cardiac diseases (especially myocardial ischaemia/reperfusion and ischaemic conditioning) in the presence and absence of major cardiovascular comorbidities and/or cotreatments. (Ferdinandy et al, European heart journal, 2018)
Figure 2: Cost of drug development during its phases. (Modified from: Ferdinandy et al. Eur Heart J, 2018)
Our major publications on the topic:
- Ferdinandy, P. et al., Definition of hidden drug cardiotoxicity: paradigm change in cardiac safety testing and its clinical implications. Eur Heart J, 2018. (link)
- Ferdinandy, P., et al., Interaction of risk factors, comorbidities, and comedications with ischemia/reperfusion injury and cardioprotection by preconditioning, postconditioning, and remote conditioning. Pharmacol Rev, 2014. 66(4): p. 1142-74. (link)
Recent achievements of undergrad researchers:
- Tamás Gergely, SCIENCE4HEALTH conference, RUDN University, Moscow, Russia, 2018, 1st prize
- Tamás Gergely, TDK conference, Budapest, Hungary, 2018, 1st prize
- Tamás Gergely, XXIII. Korányi Frigyes Tudományos Fórum, Budapest, Hungary, 2018
- Tamás Gergely, TDK conference, Marosvásárhely, Romania, 2018
Learning opportunities: literature search methods, designing in vivo rat studies, animal handling, oral treatment of small animals, performing cardiac surgeries on rats, data evaluation and presentation.
Project leader: Dr. Gábor Brenner PhD student
Effect of metabolic diseases on cardioprotective interventions and treatments against ischemia/reperfusion injury
Metabolic derangements, such as obesity or diabetes, are major risk factors of cardiovascular diseases. The healthy heart can adapt to a certain level of ischemic injury (e.g., during a heart attack), but metabolic diseases have a negative effect of this ischemia-tolerance of the heart, and may increase the extent of injury afflicted by ischemia/reperfusion. The mechanism of the changes in the myocardium due to metabolic co-morbidities are not fully understood, more detailed information on them would enable the development of novel cardioprotective therapies, which would lead to a better prognosis of ischemic heart diseases. In our Department infarction is inflicted on anesthetized rats with metabolic diseases in our state of the art small animal surgery facility (Figure 3) by a surgical procedure, where the left descending coronary artery is occluded by placing a suture around it for 30-45 min then released.
During surgery, we monitor vital parameters (e.g., blood pressure, ECG, temperature, respiration; Figure 4). Our undergraduate researchers learn surgical techniques and are involved actively in our ongoing studies.
Our publications on the topic:
- Baranyai, T., et al., Acute hyperglycemia abolishes cardioprotection by remote ischemic perconditioning. Cardiovasc Diabetol, 2015. 14: p. 151.
- Andreadou I, Iliodromitis EK, Lazou A, Görbe A, Giricz Z, Schulz R, Ferdinandy P. Effect of hypercholesterolemia on myocardial function, ischemia-reperfusion injury and cardioprotection by preconditioning, postconditioning and remote conditioning. Br J Pharmacol. 2017 Jun; 174 (12):1555-1569. (link)
- Pavo N, Lukovic D, Zlabinger K, Zimba A, Lorant D, Goliasch G, Winkler J, Pils D, Auer K, Jan Ankersmit H, Giricz Z, Baranyai T, Sárközy M, Jakab A, Garamvölgyi R, Emmert MY, Hoerstrup SP, Hausenloy DJ, Ferdinandy P, Maurer G, Gyöngyösi M. Sequential activation of different pathway networks in ischemia-affected and non-affected myocardium, inducing intrinsic remote conditioning to prevent left ventricular remodeling. Sci Rep.2017 Mar 7;7:43958.. (link)
- Nagy CT, Koncsos G, Varga ZV, Baranyai T, Tuza S, Kassai F, Ernyey AJ, Gyertyán I, Király K, Oláh A, Radovits T, Merkely B, Bukosza N, Szénási G, Hamar P, Mathé D, Szigeti K, Pelyhe C, Jelemenský M, Onódi Z, Helyes Z, Schulz R, Giricz Z, Ferdinandy. Selegiline reduces adiposity induced by high-fat, high-sucrose diet in male rats. Br J Pharmacol. 2018 Sep;175(18):3713-3726. (link)
- Koncsos G, Varga ZV, Baranyai T, Boengler K, Rohrbach S, Li L, Schlüter KD, Schreckenberg R, Radovits T, Oláh A, Mátyás C, Lux Á, Al-Khrasani M, Komlódi T, Bukosza N, Máthé D, Deres L, Barteková M, Rajtík T, Adameová A, Szigeti K, Hamar P, Helyes Z, Tretter L, Pacher P, Merkely B, Giricz Z, Schulz R, Ferdinandy P. Diastolic dysfunction in prediabetic male rats: Role of mitochondrial oxidative stress. Am J Physiol Heart Circ Physiol. 2016 Oct 1;311(4):H927-H943. (link)
Learning opportunities: literature search methods, designing in vivo rat studies, animal handling, working with metabolic disease models in rats, oral treatment of small animals, performing cardiac surgeries on rats, data evaluation and presentation.
Project leader: Dr. Gábor Brenner PhD student