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.

Reperfusion injury salvage kinase signalling: taking a RISK for cardioprotection.

Following an acute myocardial infarction (AMI), early coronary artery reperfusion remains the most effective means of limiting the eventual infarct size. The resultant left ventricular systolic function is a critical determinant of the patient's clinical outcome. Despite current myocardial reperfusion strategies and ancillary antithrombotic and antiplatelet therapies, the morbidity and mortality of an AMI remain significant, with the number of patients developing cardiac failure increasing, necessitating the development of novel strategies for cardioprotection which can be applied at the time of myocardial reperfusion to reduce myocardial infarct size.

Realizing the clinical potential of ischemic preconditioning and postconditioning.

After an acute myocardial infarction (AMI), early reperfusion by thrombolysis or primary percutaneous coronary intervention remains the most-effective strategy for limiting the size of an evolving infarct. The mortality from AMI, however, remains significant, due partly to the lethal reperfusion injury that occurs on reperfusing the ischemic myocardium. Novel cardioprotective strategies are required to target this form of injury.

Preconditioning the myocardium: from cellular physiology to clinical cardiology.

The phenomenon of ischemic preconditioning, in which a period of sublethal ischemia can profoundly protect the cell from infarction during a subsequent ischemic insult, has been responsible for an enormous amount of research over the last 15 years. Ischemic preconditioning is associated with two forms of protection: a classical form lasting approximately 2 h after the preconditioning ischemia followed a day later by a second window of protection lasting approximately 3 days. Both types of preconditioning share similarities in that the preconditioning ischemia provokes the release of several autacoids that trigger protection by occupying cell surface receptors.

Atorvastatin, administered at the onset of reperfusion, and independent of lipid lowering, protects the myocardium by up-regulating a pro-survival pathway.

Objectives: The purpose of this study was to determine whether atorvastatin, a 3-hydroxy-3-methylglutaryl (HMG)-co-enzyme A (CoA) reductase inhibitor, limits myocardial necrosis when administered as an adjunct to reperfusion.

Background: Statins inhibit HMG-CoA reductase to reduce the synthesis of cholesterol. However, it is proposed that statins have cardiovascular effects beyond their ability to lower cholesterol, possibly via recruitment of phosphatidyl inositol 3-kinase (PI3K) and the serine/threonine kinase, Akt.

Mitochondrial K(ATP) channel opening protects a human atrial-derived cell line by a mechanism involving free radical generation.

Objectives: The mechanism by which the mitochondrial K(ATP) channel openers confer protection against ischemia/reperfusion injury is debated. Evidence suggests that rather than solely being an end effector, opening of these channels may act by a trigger mechanism. We examined the effects of the mitochondrial K(ATP) channel opener, diazoxide on parameters of mitochondrial function with specific reference to reactive oxygen species (ROS) generation in a human atrial derived cell line model of simulated ischemia/reperfusion (LSI/R).

The p38 MAPK inhibitor, SB203580, abrogates ischaemic preconditioning in rat heart but timing of administration is critical.

There is debate concerning the involvement of p38 mitogen activated protein kinase (MAPK) in the mediation of ischaemic preconditioning. Pharmacological inhibition of p38 MAPK with SB203580 has been reported to block preconditioning in some studies but not in others. We hypothesised that this divergence could be due to differences in the timing of inhibitor administration.