Remote ischemic conditioning: from experimental observation to clinical application: report from the 8th Biennial Hatter Cardiovascular Institute Workshop.

In 1993, Przyklenk and colleagues made the intriguing experimental observation that 'brief ischemia in one vascular bed also protects remote, virgin myocardium from subsequent sustained coronary artery occlusion' and that this effect'...

Conditioning the whole heart--not just the cardiomyocyte.

Conditioning, the recruitment of endogenous cytoprotective pathways that protect the myocardium against injurious ischaemia/reperfusion injury, has developed into a range of modalities that can be applied before (preconditioning), during (perconditioning) or after the injurious ischaemic insult (postconditioning), either directly to the heart or in a distal tissue (remote preconditioning). A wide range of triggers, signaling pathways and potential end-effector mechanisms have been identified, which appear common to all forms of conditioning. Interestingly, conditioning applies to not only the cardiac myocyte, but to all the constitutive cell types within the myocardium.

Remote ischemic conditioning: a clinical trial's update.

Coronary artery disease (CAD) is the leading cause of death and disability worldwide, and early and successful restoration of myocardial reperfusion following an ischemic event is the most effective strategy to reduce final infarct size and improve clinical outcome. This process can, however, induce further myocardial damage, namely acute myocardial ischemia-reperfusion injury (IRI) and worsen clinical outcome. Therefore, novel therapeutic strategies are required to protect the myocardium against IRI in patients with CAD.

Necroptosis, necrostatins and tissue injury.

Cell death is an integral part of the life of an organism being necessary for the maintenance of organs and tissues. If, however, cell death is allowed to proceed unrestricted, tissue damage and degenerative disease may ensue. Until recently, three morphologically distinct types of cell death were recognized, apoptosis (type I), autophagy (type II) and necrosis (type III).

Retrograde heart perfusion: the Langendorff technique of isolated heart perfusion.

In the late 19th century, a number of investigators were working on perfecting isolated heart model, but it was Oscar Langendorff who, in 1895, pioneered the isolated perfused mammalian heart. Since that time, the Langendorff preparation has evolved and provided a wealth of data underpinning our understanding of the fundamental physiology of the heart: its contractile function, coronary blood flow regulation and cardiac metabolism. In more recent times, the procedure has been used to probe pathophysiology of ischaemia/reperfusion and disease states, and with the dawn of molecular biology and genetic manipulation, the Langendorff perfused heart has remained a stalwart tool in the study of the impact upon the physiology of the heart by pharmacological inhibitors and targeted deletion or up-regulation of genes and their impact upon intracellular signalling and adaption to clinically relevant stressful stimuli.

Failure of the adipocytokine, resistin, to protect the heart from ischemia-reperfusion injury.

Experimental studies have linked the adipocytokines with acute cardioprotection. Whether the adipocytokine, resistin, confers protection is, however, debatable. In the current study, the actions of resistin, administered at reperfusion, were investigated in in vivo and in vitro rodent and in vitro human models of myocardial ischemia-reperfusion (I/R) injury.

Mitochondrial cyclophilin-D as a potential therapeutic target for post-myocardial infarction heart failure.

The pharmacological inhibition or genetic ablation of cyclophilin-D (CypD), a critical regulator of the mitochondrial permeability transition pore (mPTP), confers myocardial resistance to acute ischemia-reperfusion injury, but its role in post-myocardial infarction (MI) heart failure is unknown. The aim of this study was to determine whether mitochondrial CypD is also a therapeutic target for the treatment of post-MI heart failure. Wild-type (WT) and CypD(-/-) mice were subjected to either sham surgery or permanent ligation of the left main coronary artery to induce MI, and were assessed at either 2 or 28 days to determine the long-term effects of CypD ablation.

Controversies in the cardiovascular management of type 2 diabetes.

In patients with type 2 diabetes mellitus, intense control of blood pressure, lipids and glucose, aiming at theoretically ideal values, is bought at a cost. Intense blood pressure control has renal complications. Intense lipid control, thus far, has worked for reduction of low-density lipoprotein-cholesterol, paradoxically at the cost of a small increase in new diabetes.

Adipocytokines, cardiovascular pathophysiology and myocardial protection.

Reducing myocardial damage resulting from ischaemia-reperfusion (I/R) is vital in ensuring patient recovery and survival. It relies upon the activation of the so-called Reperfusion Injury Salvage Kinase (RISK) pathway. Experimentally various treatments, both mechanical and chemical, have been shown to protect the myocardium against I/R injury.

The neural and humoral pathways in remote limb ischemic preconditioning.

Remote ischaemic preconditioning (RIPC) is a therapeutic intervention that has been demonstrated to reduce myocardial injury in the clinical setting. However, the underlying cardioprotective mechanisms remain unclear. We hypothesised that RIPC utilises both humoral and neural pathways to convey the cardioprotective signal from the preconditioned remote organ to the heart.

Mitochondrial cyclophilin-D as a critical mediator of ischaemic preconditioning.

Aims: It has been suggested that mitochondrial reactive oxygen species (ROS), Akt and Erk1/2 and more recently the mitochondrial permeability transition pore (mPTP) may act as mediators of ischaemic preconditioning (IPC), although the actual interplay between these mediators is unclear. The aim of the present study is to determine whether the cyclophilin-D (CYPD) component of the mPTP is required by IPC to generate mitochondrial ROS and subsequently activate Akt and Erk1/2.

Methods And Results: Mice lacking CYPD (CYPD-/-) and B6Sv129 wild-type (WT) mice were used throughout.

Blood pressure oscillations during tilt testing as a predictive marker of vasovagal syncope.

Aims: During head-up tilt (HUT) testing, a period of haemodynamic instability, marked by oscillations in blood pressure, often precedes vasovagal syncope. We hypothesized that the presence of oscillations in blood pressure during HUT testing predicts a positive diagnosis for vasovagal syncope.

Methods And Results: The haemodynamic profiles of 42 consecutive patients non-responsive to passive HUT and glyceryl trinitrate (GTN) provocation ('non-responders') and, contemporaneously, 41 consecutive patients responsive to passive HUT and GTN provocation ('responders') were assigned oscillation-positive or oscillation-negative depending on the presence or absence of a characteristic oscillation in systolic blood pressure which varied by > or =30 mmHg (peak-to-trough).

The cannabinoid CB1 receptor antagonist, rimonabant, protects against acute myocardial infarction.

CB1 antagonism is associated with reduced doxorubicin-induced cardiotoxicity and decreased cerebrocortical infarction. Rimonabant, a selective CB1 receptor antagonist, was, before it was withdrawn, proposed as a treatment for obesity and reported to reduce cardiovascular risk by improving glucose and lipid profiles and raising adiponectin levels. The cardioprotective actions of rimonabant in 6-week-old C57BL/6J mice fed either high-fat (HFD) or standard diets (STD) for 8 weeks were investigated.

Signalling pathways in ischaemic postconditioning.

Coronary heart disease (CHD) is the leading cause of death globally. Following an acute coronary artery occlusion, timely myocardial reperfusion using either primary percutaneous coronary intervention (PCI) or thrombolytic therapy remains the most effective treatment strategy for reducing myocardial infarct size, preventing left ventricular remodelling, preserving left ventricular systolic function and improving clinical outcomes. However, the full benefits of myocardial reperfusion are not realised, given that the actual process of reperfusing ischaemic myocardium can independently induce cell death - a phenomenon termed lethal reperfusion injury.

Urocortin: a protective peptide that targets both the myocardium and vasculature.

The urocortins are a family of endogenously produced peptide hormones that show great promise as potential drugs for the treatment of heart disease. They can increase contractility and cardiac output without causing changes in mean arterial blood pressure. As expected, the receptor for these peptides is present in cardiomyocytes, and they can bind and protect these cells from simulated ischemia and reperfusion in vitro.

Cardioprotective growth factors.

Many of the originally identified cardiovascular 'growth factors' have been demonstrated to exert a diverse variety of actions within the cardiovascular system, the majority of which are unrelated to their initially proposed mechanism of action. Interestingly, several of these growth factors have been demonstrated to protect the cardiomyocyte from the detrimental effects of acute ischaemia-reperfusion injury, through the activation of a variety of cell-surface receptors and the subsequent recruitment of a number of intracellular signal transduction pathways, which include components of the reperfusion injury salvage kinase pathway. This article will review several of these cardioprotective growth factors with respect to their ability to confer direct myocardial protection, focusing on the underlying signalling pathways involved and their potential for clinical application.

Platelet alpha- and beta-secretase activities: A preliminary study in normal human subjects.

beta-amyloid (Abeta) arises from an amyloid precursor protein (APP) via beta- and gamma-secretase proteolysis. Platelets are the primary depot of APP in the circulation and may be a source of cerebral Abeta. We measured the platelet activities of alpha- and beta-secretases in normal individuals.

Targeting residual cardiovascular risk: raising high-density lipoprotein cholesterol levels.

The last 20 years have witnessed dramatic reductions in cardiovascular risk using 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") to lower levels of low-density lipoprotein cholesterol (LDL-C). Using this approach one can achieve a reduction in the risk of major cardiovascular events of 21% for every 1 mmol/l (39 mg/dl) decrease in LDL-C. However, despite intensive therapy with high dose "statins" to lower LDL-C levels below 2.

Drug discovery possibilities from visfatin cardioprotection?

The adipocytokine, visfatin, exerts a diverse variety of effects that include the ability to mimic the glucose-lowering effects of insulin. In addition to its anti-hyperglycaemic action, recent evidence suggests that visfatin may be responsible for a number of different cardiovascular effects, depending on the cell type and the duration of therapy, one of which includes the ability to protect the myocardium from the detrimental effects of acute ischaemia-reperfusion injury. As such visfatin may not only provide a potential new target for acute cardioprotection but it may also act as an anti-diabetic agent with a unique mechanism of action, thereby offering a potentially novel drug target for the diabetic patient that experiences an episode of acute myocardial ischaemia-reperfusion injury.

The powerful cardioprotective effects of urocortin and the corticotropin releasing hormone (CRH) family.

The urocortins are members of the corticotropin releasing hormone (CRH) family of peptide hormones. The archetypal member of this family, CRH, plays an important role in regulating thermogenesis and homeostasis by acting centrally and systemically in target organs via its two receptors CRH-R1 and CRH-R2. However, by virtue of their much greater relative affinity for CRH-R2, the physiological effects of the urocortin peptides are largely restricted to peripheral organs such as the heart.

Ischemia-reperfusion injury and cardioprotection: investigating PTEN, the phosphatase that negatively regulates PI3K, using a congenital model of PTEN haploinsufficiency.

Activation of the PI3K/Akt pathway protects the heart from ischemia-reperfusion injury (IRI). The phosphatase PTEN is the main negative regulator of this pathway. We hypothesized that reduced PTEN levels could protect against IRI.

Targeting residual cardiovascular risk: raising high-density lipoprotein cholesterol levels.

The last 20 years have witnessed dramatic reductions in cardiovascular risk using 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") to lower levels of low-density lipoprotein cholesterol (LDL-C). Using this approach one can achieve a reduction in the risk of major cardiovascular events of 21% for every 1 mmol/l (39 mg/dl) decrease in LDL-C. However, despite intensive therapy with high dose "statins" to lower LDL-C levels below 2.

Remote ischaemic preconditioning: underlying mechanisms and clinical application.

Remote ischaemic preconditioning (RIPC) represents a strategy for harnessing the body's endogenous protective capabilities against the injury incurred by ischaemia and reperfusion. It describes the intriguing phenomenon in which transient non-lethal ischaemia and reperfusion of one organ or tissue confers resistance to a subsequent episode of lethal ischaemia reperfusion injury in a remote organ or tissue. In its original conception, it described intramyocardial protection, which could be relayed from the myocardium served by one coronary artery to another.