Myocardial Adaptation as a Novel Approach to Reduce a Risk of Heart Failing Using Clinically Relevant Methods

Despite the progress in pharmacotherapy, interventional cardiology (PPCI) and cardiac surgery of acute myocardial infarction (AMI), gradual post-AMI progression of myocardial dysfunction leads to heart failure (HF). Its increasing incidence represents a serious danger especially in the elder population challenged with further comorbidities, the prognosis being more unfavourable in females. Pathophysiological mechanisms of HF are complex and involving processes such as hemodynamic overload, ischemia, fibrosis, inflammation, ventricular remodelling, neurohumoral disbalanse, altered gene expression and Ca2+ cycling, oxidative stress, acceleration of apoptosis and mitochondrial dysfunction that subsequently leads to progressive decline of heart function and increased morbidity and mortality. Currently, neither effective prevention of AMI nor ultimate reduction of ischemia/ reperfusion (I/R) injury is available, therefore, there is an urgent need to search for alternative approaches based on the experimental findings. Ischemic preconditioning (PC) is a most robust form of innate cardioprotection based on the adaptation of the heart to I/R, which translation to clinical practice has been relatively successful albeit limited by technical requirements and short-term duration. Nevertheless, novel forms of adaptive interventions such as „remote“ PC (RPC) appear as promising beneficial approaches. Although molecular mechanisms of RPC are not yet completely elucidated, some forms of RPC, in particular its non-invasive modifications, have been already used in clinical conditions in patients with AMI, PPCI, congentital defects and bypass surgery, albeit with different effectiviness. We assume that in contrast to a traditional approach to pharmacological treatment of HF often focused on only one pathophysiological mechanism, a complex targeting of several pathophysiological mechanisms upon activation of intrinsic adaptive pathways represents a platform for the development of novel strategies to fight HF. Tanya Ravingerova* Department of Cardiovascular Physiology and Pathophysiology, Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovak Republic Tanya Ravingerova Journal of Heart and Stroke Remedy Publications LLC. 2017 | Volume 2 | Issue 2 | Article 1022 2 10], cardiotoxicity subsequent to chemotherapy and radiotherapy in oncological patients [11,12], overload of hearts muscle in valvular diseases (regurgitation), chronic rhythm disorders (tachyarrhytmias) [13], or hypertrophy of the heart pumping against increased resistance in peripheral arteries in hypertension [14,15], all these factors contribute to the development of chronic HF. Impact of Gender and Aging on the Development of Heart Failure Incidence of cardiac ailments differs with gender and age [1618]. It has been shown that the risk for developing heart failure is twice as high in males compared to females in the age group between 55 and 64, and several epidemiological studies have confirmed that pre-menopausal women have a reduced risk of CVD [17,18]. On the other hand, over the age of 65, both genders have the same risk for developing heart failure [19] and in females, the risk of HF is increasing even more than in males. This is attributed to the cardioprotective properties of ovarian hormones [20] and to the fact that their insufficiency also contributes to the development of hypertension, diabetes and hyperlipidemia [18]. However, this remains underestimated and often leads to improper management of AMI in females including late hospital attendance and the onset of revascularization interventions, as well as other adverse consequences leading to development of HF [19]. Despite that, much research effort (clinical and experimental) to date has been focused on the investigation of cardioprotection mostly in healthy male subjects of adult age although gender differences play an important role in the heart response to ischemia and subsequent preservation/ deterioration of heart function, in particular, in elder population [20]. Our recent studies demonstrated gender-related rat heart response to ischemia associated with age [21,22] that has been manifested already during maturation, while gender differences with respect to ischemic tolerance were present even in the juvenile animals. Management of Heart Failure Pathophysiological mechanisms of HF are complex and heterogenous involving processes such as hemodynamic overload, ischemia, fibrosis, inflammation, ventricular remodelling, neurohumoral disbalanse, altered gene expression and Ca2+ cycling, oxidative stress, acceleration of apoptosis and mitochondrial dysfunction that subsequently lead to progressive decline of heart function and increased morbidity and mortality [23,24]. One of the important strategies to combat heart failure is to treat the initial disease that caused heart failure in the first instance, followed by supporting cardiac activity and cardioprotection. The treatment can be either pharmacological, instrumental (cardiac device), surgical or as a last option – heart transplantation. As the most common reason of heart failing is IHD and AMI, early restoration of blood flow in the ischemic myocardium is a prerequisite for its salvage. On the other hand, delayed revascularization may lead to ischemia/reperfusion (I/R) injury [25]. Despite improved pharmacological and cardiac device therapies, neither effective prevention of AMI nor reduction of I/R injury is currently available. Thus, there is a substantial unmet need for novel approaches, ideally those, that specifically address repair and regeneration of damaged and/or lost myocardium (given limited endogenous repair of cardiomyocytes in adults). Current trends of alternative approaches to management of patients suffering from multiple ailments leading to heart failure differ from traditional pharmacological treatment often focused on targeting only one pathophysiological mechanism. We assume that in contrast to that, a complex targeting of several pathophysiological mechanisms represents a platform for the development of novel strategies to fight HF. Short-term Cardiac Adaptation – Ischemic Preconditioning It has been revealed in numerous experimental and clinical studies that some stressful stimuli (e.g., transient episodes of ischemia/hypoxia, reactive oxygen species) exert not only deleterious effects but also trigger short-term or longer lasting adaptive processes in the heart, which ensue in greater resistance against IR injury. The concept of heart’s own protection is based on the principle that short-term cardiac adaptation to certain forms of moderate stress increases resistance of the heart against subsequent sustained ischemia – phenomenon of preconditioning (PC). Ischemic PC has been observed in all animal species including humans [26,27]. It is manifested by a delay of necrotic and apoptotic processes in the cardiomyocytes [3], reduction of lethal arrhythmias [28] and by an improved post-I/R functional recovery [16,29]. Unfortunately, in clinical situations, application of classical ischemic PC has certain limitations, due to its short-term duration, whereby the occurrence of AMI is unpredictable, or due to requirement of chest opening (to get access to coronary arteries) that can be possible to perform only by trained personnel in the specialized hospitals. Clinically Applicable Forms of Preconditioning On the other hand, novel forms of PC appear to be perspective from the clinical point of view. One of these novel forms is so called remote ischemic preconditioning (RPC), in which induction of ischemia in any organ confers protection to other, distant organs/ tissues [25,30,23,24]. It is important to note that animal(and some clinical) studies documented a beneficial effect of brief episodes of limb ischemia leading to cardiac protection against I/R [31-33]. This non-invasive modification of RPC does not require invasive surgery (such as chest opening), and thus, can be applied even in the ambulance or during the transportation of a patient to the hospital. These interventions include inflation (200 mmHg) and deflation of a pressure cuff placed on an upper or lower limb and realized in three 5-min cycles. Moreover, in relation to ischemia, RPC may be applied in settings of pre-, peror post-conditioning (after the end of ischemia during surgical interventions). Its similar effectiveness in these settings offers relatively great time window for its realization, in contrast to classical ischemic PC, that makes RPC more attractive from the clinical point of view. In particular, non-invasive and easy application of RPC (limb ischemia, 33) has been started to be implemented in clinical conditions, e.g., in treatment of patients with AMI [34,35]. Beneficial effects of RPC have been also demonstrated during surgical interventions in children with congentital heart defects [36]. Further important breakthrough was a finding that with respect to the effect of RPC on the HF progression, this intervention could be applied not only in the acute setting of several bouts of limb ischemia, but it could be also administered as repeated cycles of limb I/R in the long-term that increases the efficiency of RPC: reduces the extent of ventricular remodelling and mortality over 28 days after AMI in a rat Tanya Ravingerova Journal of Heart and Stroke Remedy Publications LLC. 2017 | Volume 2 | Issue 2 | Article 1022 3 in vivo model [37]. Similarly, repeated RPC increased endotheliumdependent vasodilatation in healthy humans and in pacients with chronic HF [38]. Thus, we may assume that this approach will enhance positive effect of RPC with respect to suppression of HF development. Potential Mechanisms of RPC Mechanisms of RPC have not been investigated in details so far, however, it is suggested that RPC triggers complex humoral and neuronal signaling leading not only to an increased resistance to I/R in a distant organ, but also a