Number 29, 2006
Bypass surgery for coronary artery disease: a vanishing treatment?
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Sexual Dysfunction and Cardiac Risk (the Second Princeton Consensus Conference)
Kostis JB, Jackson G, Rosen R, et al. Am J Cardiol. 2005;96:313–321.
Recent studies have highlighted the relation between erectile dysfunction (ED) and cardiovascular disease. In particular, the role of endothelial dysfunction and nitric oxide in ED and atherosclerotic disease has been elucidated. Given the large number of men receiving treatment for ED, concerns regarding the risk for sexual activity triggering acute cardiovascular events and potential risks of adverse or unanticipated drug interactions need to be addressed. A risk stratification algorithm was developed by the First Princeton Consensus Panel to evaluate the degree of cardiovascular risk associated with sexual activity for men with varying degrees of cardiovascular disease. Patients were assigned to three categories: low, intermediate (including those requiring further evaluation), and high risk. This consensus study from the Second Princeton Consensus Conference corroborates and clarifies the algorithm and emphasizes the importance of risk factor evaluation and management for all patients with ED. The panel reviewed recent safety and drug interaction data for three phosphodiesterase (PDE)-5 inhibitors (sildenafil, tadalafil, vardenafil), with emphasis on the safety of these agents in men with ED and concomitant cardiovascular disease. Increasing evidence supports the role of lifestyle intervention in ED, specifically weight loss and increased physical activity, particularly in patients with ED and concomitant cardiovascular disease. Special management recommendations for patients taking PDE-5 inhibitors who present at the emergency department and other emergency medical situations are described. Finally, further research on the role of PDE-5 inhibition in treating patients with other medical or cardiovascular disorders is recommended.
Commentary
The First Princeton Consensus Conference in 1999 established important guidelines for evaluating cardiac patients and counseling them on the safety of sexual intercourse and the treatment of erectile dysfunction. The Second Conference updated those guidelines and reviewed in detail the treatments available for erectile dysfunction. In this paper, the phosphodiesterase type-5 inhibitors are discussed from the point of view of being both a treatment for erectile dysfunction and an exciting form of cardiovascular therapy. Management recommendations include risk assessment and specific disease advice; the cardiac safety of treatments of erectile dysfunction is also considered, supported by two practical algorithms. There is a statement on hypogonadism and testosterone treatment, and emphasis on the importance of primary care management, prevention and lifestyle modification – “towards a patient-centred approach”. With vascular disease recognized as the most important cause of erectile dysfunction, and erectile dysfunction being in turn recognized as a marker of cardiovascular risk in men with erectile dysfunction but no cardiac history, these guidelines are essential reading for all involved in treating cardiac patients and those with erectile dysfunction.
Graham Jackson
Downregulation of peroxisome proliferator-activated receptor-alpha gene expression in a mouse model of ischemic cardiomyopathy is dependent on reactive oxygen species and prevents lipotoxicity
Dewald O, Sharma S, Adrogue J, et al. Circulation. 2005;112:407–415.
The peroxisome proliferators-activated receptor-α (PPARα), a transcription factor that modulates fatty acid metabolism, regulates substrate preference in the heart. In acute ischemia there is a switch in substrate preference from fatty acids to glucose, but the expression of metabolic genes in repetitive ischemia is not well described. In a mouse model of ischemic cardiomyopathy induced by repetitive ischemia/reperfusion, we postulated that downregulation of PPARα is regulated by reactive oxygen species and is necessary for maintaining contractile function in the heart.
Repetitive closed-chest ischemia/reperfusion (15 min) was performed daily in C57/BL6 mice, mice overexpressing extracellular superoxide dismutase, and mice treated with the PPARα agonist, WY-14,643. Echocardiography, histology, and expression of candidate genes were measured at 3, 5, 7, and 28 days of repetitive ischemia/reperfusion and 15 and 30 days after discontinuation of the ischemia/reperfusion. Repetitive ischemia/reperfusion was associated with a downregulation of PPARα-regulated genes and levels of both myosin heavy chain isoform transcripts, which was reversible on discontinuation of ischemia/reperfusion. Overexpression of extracellular superoxide dismutase prevented the downregulation of PPARα-regulated genes and myosin isogenes by repetitive ischemia/reperfusion. Furthermore, reactivation of PPARα in mice exposed to repetitive ischemia/reperfusion worsened contractile function, induced microinfarctions, and increased the intramyocardial deposition of triglyceride – features suggestive of cardiac lipotoxicity.
We conclude that the expression of metabolic and myosin isoform genes in repetitive ischemia/reperfusion is mediated by reactive oxygen species. Furthermore, we suggest that downregulation of PPARα in repetitive ischemia/reperfusion is an adaptive mechanism that is able to prevent lipotoxicity in the ischemic myocardium.
Commentary
The heart normally metabolizes a balance of fatty acids and carbohydrates to support the high energy demands of the heart. In severe hypertrophy and heart failure, this balance of fuel use is shifted, such that fatty acid metabolism is decreased and the heart shifts to using a greater amount of glucose as a source of energy. This shift in energy metabolism is accompanied by alterations in the expression of metabolic genes, such that genes that modulate fatty acid metabolism are downregulated whereas genes controlling glucose metabolism are upregulated. An important nuclear transcriptional factor controlling this process is PPARα. A decrease in PPARα decreases the expression of a number of genes of fatty acid metabolism in cardiac hypertrophy and heart failure. The hibernating myocardium – a condition characterized by a reversible cardiac dysfunction – also shows a decrease in the expression of genes controlling fatty acid metabolism. What was not clear is whether this downregulation of genes controlling fatty acid metabolism contributes to contractile dysfunction in hibernating myocardium, cardiac hypertrophy, or heart failure. This study by Dewald et al provides compelling data to show that downregulation of fatty acid metabolic genes in a mouse experimental model of repetitive ischemia and reperfusion is an adaptive mechanism that is able to protect the heart. They also show that reactivation of the expression of genes of fatty acid metabolism (by treatment of mice with a PPARα agonist) worsens contractile function, induces microinfarctions, and increases intramyocardial accumulation of lipid. These data suggest that downregulation of fatty acid metabolism in hibernating myocardium is an adaptive mechanism, and that the modulation of metabolism to inhibit fatty acid oxidation may provide a pharmacological target for cardioprotection in repetitive ischemia and reperfusion.
Gary Lopaschuk
Reperfusion-induced translocation of δPKC to cardiac mitochondria prevents pyruvate dehydrogenase reactivation
Churchill EN, Murriel CL, Chen C-H, Mochly-Rosen D, Szweda LI. Circ Res. 2005;97:78–85.
Despite the disparity in evidence regarding pyruvate dehydrogenase (PDH) activity, cardiac efficiency and recovery of contractile function in postischemic hearts can be improved by pharmacological stimulation of PDH or infusion of pyruvate. Therefore, identification of factors that regulate PDH activity during ischemia/reperfusion may enhance the potential for therapeutic intervention. PDH is responsible for the conversion of pyruvate derived from glycolysis to acetyl coenzyme A for Krebs cycle activity and represents a highly regulated and critical site for the control of glycolytic flux and the production of ATP. Enzyme activity is regulated, in part, by phosphorylation- and dephosphorylation-dependent inhibition and activation, respectively. The aim of this study was to investigate signaling mechanisms that control inhibition and reactivation of PDH during reperfusion. We tested the hypothesis that the redox-sensitive δ-isoform of protein kinase C (δPKC) is involved in regulation of PDH during reperfusion. Rat hearts were perfused in the Langendorff mode, and a specific peptide inhibitor of δPKC was used to test the contribution of δPKC to ischemia- and reperfusion-induced alterations in PDH activity. In addition, hearts were infused with H2O2 to gain insight into potential mechanisms responsible for concerted regulation of δPKC and PDH during ischemia/reperfusion. Finally, in-vitro experiments were performed to address potential mechanisms by which δPKC influences the phosphorylation state of PDH.
Commentary
PDH was shown to decline in activity during cardiac ischemia. Although a fractional regain in PDH activity occurred on reperfusion, the activity of the enzyme remained depressed relative to control values. δPKC translocated to the mitochondria during reperfusion, and prevention of δPKC translocation resulted in complete recovery in PDH activity. Thus δPKC prevents reactivation or promotes continued inhibition of PDH (or both) in response to cardiac reperfusion. Reperfusion of ischemic myocardium is associated with enhanced generation of free radicals, and pro-oxidants have been shown to regulate protein function either directly or indirectly through the modulation of other regulatory molecules, one example of which is the novel δ-isoform of PKC. Infusion of the δPKC activator H2O2 during normoxic perfusion, to mimic one aspect of cardiac reperfusion, resulted in a loss of PDH activity that was largely attributable to translocation of δPKC to the mitochondria. Evidence indicates that reperfusion-induced translocation of δPKC is associated with phosphorylation of one subunit (the E1α subunit) of PDH, and this phosphorylation inhibits its activity. In this study, H2O2-dependent loss of PDH activity was partially prevented by the inhibition of δPKC translocation. In contrast, prevention of translocation of δPKC to the mitochondria during reperfusion resulted in full reactivation of PDH. This difference may be explained by previous findings that translocation of δPKC to the mitochondria results in release of cytochrome c that could, in turn, amplify mitochondrial production of free radicals. Thus prevention of translocation of δPKC to the mitochondria during reperfusion would be expected to prevent δPKC- and redox-dependent inhibition of PDH.
Danielle Feuvray
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