Publications

Signaling pathways involving protein kinase C isozymes are modulators of cardiovascular development and response to injury. Protein kinase C epsilon activation in cardiac myocytes reduces necrosis caused by coronary artery disease. However, it is unclear whether protein kinase C epsilon function is required for normal cardiac development or inducible protection against oxidative stress. Protein kinase C delta activation is also observed during cardiac preconditioning. However, its role as a promoter or inhibitor of injury is controversial. We examined hearts from protein kinase C epsilon knock-out mice under physiological conditions and during acute ischemia reperfusion. Null-mutant and wild-type mice displayed equivalent base-line morphology and hemodynamic function. Targeted disruption of the protein kinase C epsilon gene blocked cardioprotection caused by ischemic preconditioning and alpha(1)-adrenergic receptor stimulation. Protein kinase C delta activation increased in protein kinase C epsilon knock-out myocytes without altering resistance to injury. These observations support protein kinase C epsilon activation as an essential component of cardioprotective signaling. Our results favor protein kinase C delta activation as a mediator of normal growth. This study advances the understanding of cellular mechanisms responsible for preservation of myocardial integrity as potential targets for prevention and treatment of ischemic heart disease.

An economic analysis was conducted using clinical outcomes in the MIRACL trial that evaluated high-dose atorvastatin versus placebo for 16 weeks after acute coronary syndrome. The direct cost of atorvastatin was largely offset by the associated decrease in cardiovascular events. The net incremental cost of atorvastatin treatment was 157 dollars/patient with a cost-effectiveness ratio of 4,086 dollars/event avoided.

Patients who survive an acute coronary syndrome of unstable angina or myocardial infarction are at much higher risk of a recurrent event within the following year than patients with stable coronary syndromes. Statin therapy is justified for many of these patients, not only for long-term benefit but also to reduce the risk of recurrent events within weeks of the primary event. The mechanisms that underlie this benefit are probably related to improvements in endothelial function, a decrease in vascular inflammation, and reduced prothrombotic factors. The effects of statins may be mediated by cholesterol reduction, cholesterol-independent effects (particularly decreasing isoprenoids), and mechanisms that are independent of inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase. Observational studies consistently show an early reduction in mortality with statin therapy started before discharge from hospital after an acute coronary syndrome. Several randomized controlled trials also support an early benefit of risk reduction from statins started during the hospital admission for an acute coronary syndrome. Early statin therapy is also related to improved compliance and use of statins several years after a coronary event. Thus, early statin therapy may improve both early and long-term secondary prevention efforts.