Cardiology Research and Practice in the application of ACE2 in central nervous system. Xiao et al. (2011) showed that central ACE2 overexpression applies a considerable cardiac protective eﬀect in the mice model of HF which was associated with a signiﬁcant decrease in sympathetic biomarkers [87]. Brain selective human ACE2 over expression also showed to be eﬀective for management of hypertension in transgenic mice [88]. Direct eﬀects of central ACE2 treatment on HF improvement and also its role in hypertension attenuation are both acceptable evidence for the eﬃcacy of ACE2 on HF management. Arrhythmia also may occur in the patients with HF and can worsen the structural and functional status of the heart in these patients. The protective eﬀect of ACE2 against arrhythmia in the failed heart is a subject of debate. The importance of the balance between ACE-Ang II-AT1R axis and the ACE2-Ang 1–7-Mas receptor axis in the regulation of heart cell volume has been suggested [89]. The key role of Ang 1–7 in decreasing the cell volume which results in decline in activation of swelling-activated chloride current (IClswell) suggesting a likely contribution of ACE2 in prevention of major post-ischemic cardiac arrhythmias [89]. However, De Mello (2009) mentioned the probable eﬀect of overexpressed ACE2 on generation of early afterdepolarization especially in the patients with HF [90]. Regarding the probable arrhythmogenic eﬀects of ACE2 in the patients with HF, it seems that precise dose adjustment based on the severity of HF may prevent this side eﬀect. There is growing interest regarding the protective role of apelin in HF development. Apelin level is considerably reduced in the patients with HF [91–93]. Several studies showed high expression of apelin/APJ in the heart and in vascular systems of rodents and humans [24, 93, 94]. The mechanisms by apelin reduction causes HF are becoming clearer. Gao et al. (2009) reported signiﬁcant increase of apelin as an indicator of improved cardiac function from 3 to 21 days after bone marrow mononuclear cell transplantation in the patients with HF through autocrine and paracrine mechanisms [92]. Apelin reduces left ventricular preload and afterload in rodents [95] and is known to be a strong positive inotropic agent [53, 94, 96] that could be outstandingly helpful in treatment of HF. Apelin mutant mice develop HF associated with aging and pressure overload [97]. Infusion of apelin-13 [98] and apelin-12 [99] enhances myocardial function of the left anterior descending artery ligation model of HF in rats. Perfusion of isolated rat hearts with apelin- 16 caused an inotropic eﬀect with a similar time course to endothelin-1 [94]. Interestingly, apelin can present a grad- ually developing but sustained inotropic eﬀect [94], which is a signiﬁcant diﬀerence compared to classical β-adrenergic eﬀects. Apelin administration to the rats in ischemic HF sig- niﬁcantly attenuates diastolic dysfunction [96]. The involve- ment of phospholipase-C, PKC, Na+/H+ and Na+/Ca2+ pumps has been proved in positive inotropic eﬀects of apelin [94, 100, 101]. The interaction between apelin and two important regulatory pumps has been proposed to be contributed to increased inotropic eﬀects of apelin by restoration of calcium in the cardiomyocyte cytosol. Japp et al. (2010) investigated the acute cardiovascular eﬀect of intrabrachial infusion of (Pyr (1)) apelin-13 in the 7 patients with chronic HF and healthy volunteers and found vasodilatation in patients and control subjects [102]. Sys- temic infusions of (Pyr(1)) apelin-13 (30 to 300 nmol/min) result in elevated cardiac index, lowered mean arterial pressure and peripheral vascular resistance in HF patients and healthy control subjects [102]. Intracoronary bolus of apelin-36 leads to increased coronary blood ﬂow and reduced peak and end-diastolic left ventricular pressures [102]. These remarkable peripheral and coronary vasodilatation eﬀects of apelin and also its eﬀect on cardiac output increase shows apelin as a novel medication for the patients with HF. Decreased density of apelin receptors in the heart tissues with cardiomyopathy may block the inotropic eﬀect of apelin on the heart [53]. APJ gene also has been suggested as a modiﬁer gene for idiopathic dilated cardiomyopathy [103]. Further investigations should focus on combination of apelin therapy with apelin receptor agonists. Synergetic eﬀects of apelin with APJ agonists may increase the eﬃcacy of apelin therapy for the patients with HF. However, these ﬁndings are not consistent with Atluri et al. (2007) ﬁndings in rats [98]. Atluri et al. (2007) showed increased APJ protein levels in myocardium of the rats with HF [98]. Pitkin et al. (2010) suggested [Glp65,Nle75,Tyr77][125I]-apelin-13 as a potent agent with high-aﬃnity, saturable and reversible aﬀect which might reﬂect its therapeutic eﬃcacy in future [53]. The diﬀerence between APJ in myocardium and arterial system of the HF patients is not completely deﬁned. Due to the dual ionotropic and hypotensive eﬀects of apelin on the patients with HF, we need to be cautious about the application of this agent in the clinical setting. APJ agonist drugs may increase the eﬃcacy of apelin therapy in the HF patients; however it is not clear whether APJ agonist drugs will increase the arterial hypotensive eﬀects of apelin. Exper- imental evidence has established an association between Ang II and development of HF [45, 81]. Chun et al. (2008) proved that apelin signaling can antagonize Ang II actions in vascu- lar disease by NO production and inhibiting Ang II cellular signaling [104]. Generally, apelin modulates Ang II-induced cardiovascular ﬁbrosis [105] which may be linked to apelin ability to inhibit the plasminogen activator inhibitor type-1 production resulting in secondary changes in the expression of matrix proteins and degrading enzymes [105]. Apelin- 13 inhibits Ang II-induced vascular contraction mainly through NO-dependent pathways [106]. There is evidence that apelin can be increased by blocking RAS [107] which may contribute to AT1 blocker treatment in the clinical setting [108]. This evidence led to the notion that apelin therapy may ameliorate RAS-related HF aggravating eﬀects. Acknowledgments S. M. Kazemi-Bajestani is supported by the STEADI-HF training program and W. Wang is supported by a studentship award from the Mazankowski Alberta Heart Institute. G. Y. Oudit is a Clinician-Investigator of the Alberta Innovates— Health Solutions and the Distinguished Clinician Scientist of the Heart and Stroke Foundation of Canada and Canadian Institutes of Health Research.