Cardiovascular research
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Cardiovascular research · Sep 2012
Cardioprotection evoked by remote ischaemic preconditioning is critically dependent on the activity of vagal pre-ganglionic neurones.
Innate mechanisms of inter-organ protection underlie the phenomenon of remote ischaemic preconditioning (RPc) in which episode(s) of ischaemia and reperfusion in tissues remote from the heart reduce myocardial ischaemia/reperfusion injury. The uncertainty surrounding the mechanism(s) underlying RPc centres on whether humoral factor(s) produced during ischaemia/reperfusion of remote tissue and released into the systemic circulation mediate RPc, or whether a neural signal is required. While these two hypotheses may not be incompatible, one approach to clarify the potential role of a neural pathway requires targeted disruption or activation of discrete central nervous substrate(s). ⋯ These data indicate a crucial dependence of RPc cardioprotection against ischaemia/reperfusion injury upon the activity of a distinct population of vagal pre-ganglionic neurones.
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Cardiovascular research · May 2012
ReviewThe coronary circulation in cardioprotection: more than just one confounder.
Cardioprotection, i.e. the reduction in infarct size by pre-, post-, or remote conditioning, has originally been characterized in young and healthy experimental animals. Over the last two decades many signalling steps of cardioprotection have been identified, again in young and healthy animals. Although proof-of-concept studies unequivocally demonstrated the recruitment of all forms of cardioprotection in humans, the translation of cardioprotection to clinical routine has been poor. ⋯ The recruitment of collateral blood flow also contributes to protection from infarction. Finally, the coronary microcirculation is also a target of both injury by myocardial ischaemia/reperfusion and protection from it. Different manifestations of coronary artery disease, such as coronary stenosis or coronary microembolization, impact on both injury and protection.
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Cardiovascular research · May 2012
Endogenous cardioprotection by ischaemic postconditioning and remote conditioning.
Persistent myocardial ischaemia causes cell death if not rescued by early reperfusion. Millions of years in nature's laboratory have evolved protective responses that 'condition' the heart (and other tissues) to adapt to stressors, and these responses are applicable to the relatively new societal stress of myocardial ischaemia and reperfusion injury. Conditioning can be applied before (preconditioning), during (perconditioning), or after (postconditioning) the ischaemic stressor by imposing short periods of non-lethal ischaemia separated by brief periods of reperfusion. ⋯ The potential downsides of imposing even brief ischaemia directly on the heart somewhat tempered the enthusiasm for applying conditioning stimuli to the heart, but this hurdle was surmounted by applying ischaemia to remote organs and tissues in pre-, per-, and postconditioning. Although the clinical translation of remote per- and postconditioning has been rapid compared with classical preconditioning, there are numerous basic questions that require further investigation, and wider adoption awaits large-scale randomized clinical trials. Pharmacological mimetics may provide another important therapeutic approach by which to treat evolving myocardial infarction.
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Cardiovascular research · Apr 2012
Receptor activator of nuclear factor-κB ligand is a novel inducer of myocardial inflammation.
Although increased levels of myocardial receptor activator of nuclear factor (NF)-κB ligand (RANKL) have been reported in heart failure, the role of this pathway in mediating activation of inflammatory pathways during myocardial remodelling is less well understood. This study sought to determine the role of myocardial RANKL in regulating cytokine expression. ⋯ Our data demonstrate for the first time that the pressure-overloaded myocardium generates RANKL, which induces TNF-α, IL-1α, and IL-1β production via a RANK-TRAF2/TRAF6-PLC-PKC-NF-κB-mediated autocrine mechanism.
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Cardiovascular research · Mar 2012
Regulation of β-adrenergic control of heart rate by GTP-cyclohydrolase 1 (GCH1) and tetrahydrobiopterin.
Clinical markers of cardiac autonomic function, such as heart rate and response to exercise, are important predictors of cardiovascular risk. Tetrahydrobiopterin (BH4) is a required cofactor for enzymes with roles in cardiac autonomic function, including tyrosine hydroxylase and nitric oxide synthase. Synthesis of BH4 is regulated by GTP cyclohydrolase I (GTPCH), encoded by GCH1. Recent clinical studies report associations between GCH1 variants and increased heart rate, but the mechanistic importance of GCH1 and BH4 in autonomic function remains unclear. We investigate the effect of BH4 deficiency on the autonomic regulation of heart rate in the hph-1 mouse model of BH4 deficiency. ⋯ Reduced GCH1 expression and BH4 deficiency cause tachycardia through enhanced β-adrenergic sensitivity, with no effect on vagal function. GCH1 expression and BH4 are novel determinants of cardiac autonomic regulation that may have important roles in cardiovascular pathophysiology.