6 ACS have been proved without any relation with structural dysfunction of the heart. The therapeutic eﬀect of apelin in the management of patients with ACS has not been examined. Evaluation of apelin role before and after acute events and its role in plaque stabilization seems to be complicated in animals, as there is no model of unstable atherosclerotic plaque-induced ACS. The precise role of ACE2 in protection of the heart and kidney against ischemia-reperfusion (I/R) injury has not been elucidated. However, according to the association between ACE2 and MAPK [61], ACE2 protective eﬀects against I/R injury seem probable. Simpkin et al. (2007) for the ﬁrst time demonstrated the protective eﬀects of apelin against I/R injury in rodents through the reperfusion injury salvage kinase (RISK) pathway activation [71]. In murine Langendorﬀ model of I/R injury, apelin-13 could increase Akt and ERK1/2 phosphorylation as well as increase Akt activity at 5 and 10 min of reperfusion [72]. Activation of Akt and ERK1/2, two important members of RISK pathway, can potentially protect the heart against I/R injury [72]. Administration of apelin can partly block the ER stress-dependent apoptosis activation in rat models of I/R injury at 2 h of reperfusion which results in the heart protection against I/R injury [72]. This protection against I/R injury remained signiﬁcant during time-related changes at 24 h of reperfusion [72]. Administration of apelin (30 pM) in Langendorﬀ model of perfused isolated rat hearts favorably preserves the impaired cardiac function [73]. In rat cultured cardiomyocytes, the antioxidant activity of apelin is thought to be largely due to inhibition of ROS production, malonaldehyde activity and lactate dehydrogenase leakage and also activation of superoxide dismutase [73]. According to several previous investigations, apelin can considerably protect the heart against I/R injury. However, apelin eﬀects against I/R injury have not been tested in humans. This promising eﬀect of apelin can be applied in humans in the conditions that I/R injury can impair the heart function and might be a leading cause of HF. Application of apelin during the percutaneous coronary intervention and coronary artery bypass graft immediately and in early days after the procedure may have therapeutic beneﬁts. 7. Role of ACE2 and Apelin in Arrhythmias Atrial ﬁbrillation (AF) is one of the most common arrhyth- mias among the patients with cardiovascular diseases. Down- regulation of both the mRNA and protein level of ACE2 has been shown to be associated with the development of AF in a rapid pacing-induced model [74]. They also showed higher expression of ERK1/2 cascade and also increased expression of collagen I protein in the atrial tissues with AF that is related to increased local Ang II [74]. It could be concluded that ACE2 treatment can easily protect the heart against the AF complications including ﬁbrosis and remodeling. However the results of Donoghue et al. paper (2003) seem contradictory [75]. Donoghue et al. (2003) reported that ACE2 overexpression in the heart leads to probable gap junction remodeling, resulting in severe electrophysiological Cardiology Research and Practice disturbances (sustained ventricular tachycardia and terminal ventricular ﬁbrillation) and high incidence of sudden death in transgenic mice [75]. The results of Donoghue et al. has not been conﬁrmed again by other studies, and several investigations have used ACE2 transgenic mice without increased sudden cardiac death. Serum apelin levels are lower in the patients with AF compared to controls [76, 77]. Falcone et al. (2010) measured apelin in 93 patients with persistent AF before successful external electrical conversion. Patients with apelin levels below the median showed a hazard ratio of 3.1 of arrhythmia recurrence compared to those with high apelin levels [78]. Low plasma apelin is an independent prognostic factor for arrhythmia recurrence in the patients with AF under antiar- rhythmia medication [78]. Apelin, due to its eﬀect on the propagation of action potential and contractility in cardiom- yocytes, is thought to modulate the pathophysiology of AF [79]. Apelin increases sarcomere shortening in normal as well as failing cardiomyocytes [79]. Moreover, apelin augments conduction velocity in monolayers of cultured neonatal rat cardiac myocytes [79]. According to our knowledge, the level of apelin has been investigated only in the patients with AF, and other forms of arrhythmia have not been investigated. 8. Role of ACE2 and Apelin in HF: Therapeutic Potentials The relationship between ACE2 deﬁciency and failure of heart function including pathological hypertrophy, ventricu- lar remodeling, and systolic dysfunction is well described [6, 80, 81]. In ACE2 deﬁcient mice model of pressure overload, increased Ang II leads to severe cardiac hypertrophy [80, 82], increased activity of MAPK [82], activation of the NADPH oxidase system and oxidative stress-induced augmented MMP-mediated degradation of the extracellular matrix [80]. rhACE2 has antiﬁbrosis properties and may attenuate expression of Ang II-induced procollagen, transforming growth factor-β1, and ﬁbronectin [6]. The attenuating eﬀect of rhACE2 on systolic and diastolic dysfunction [6, 81] is thought to be largely due to Ang II inhibition [6]. rhACE2 treatment blocks the Ang II-mediated activation of PKC- α, PKC-β1, ERK 1/2 and JAK-STAT in wild-type mice [6]. Ferreira et al. (2011) showed that chronic XNT infusion, an ACE2 activator, was associated with decreased cardiac collagen content, increased cardiac Ang 1–7 immunostaining and a reduction in ERK phosphorylation [83]. Ang 1–9, a known product of ACE2 activity in RAS, results in consider- able reduced hypertension-induced cardiac ﬁbrosis through modulation of collagen I expression [84]. Furthermore, Ang 1–9 attenuates Ang II-inducfed cardiomyocyte hypertrophy [85]. ACE2 by inhibiting several remodeling pathways can attenuate Ang II and pressure-overload-induced cardiomy- opathy. In HF there is hyperactivity of the sympathetic nervous system which chronically may have adverse eﬀect on cardiac function. ACE2, Ang 1–7, and the Mas receptor exist in the brain; however, controversy remains over their relation with the cardiovascular functions [86]. There is growing interest