Vol. 218, No. 6, June 2014
9. Lassaletta AD, Chu LM, Robich MP, et al. Overfed ossabaw swine with early stage metabolic syndrome have normal coronary collateral development in response to chronic ischemia. Basic Res Cardiol 2012;107:243. 10. Whelan RS, Kaplinskiy V, Kitsis RN. Cell death in the pathogenesis of heart disease: mechanisms and significance. Ann Rev Physiol 2010;72:19e44. 11. Perrelli MG, Pagliaro P, Penna C. Ischemia/reperfusion injury and cardioprotective mechanisms: role of mitochondria and reactive oxygen species. World J Cardiol 2011;3: 186e200. 12. Konstantinidis K, Whelan RS, Kitsis RN. Mechanisms of cell death in heart disease. Arterioscleros Thromb Vasc Biol 2012; 32:1552e1562. 13. Lam EW, Francis RE, Petkovic M. Foxo transcription factors: key regulators of cell fate. Biochemic Soc Trans 2006;34: 722e726. 14. Towler MC, Hardie DG. Amp-activated protein kinase in metabolic control and insulin signaling. Circ Res 2007;100: 328e341. 15. Terai K, Hiramoto Y, Masaki M, et al. Amp-activated protein kinase protects cardiomyocytes against hypoxic injury through attenuation of endoplasmic reticulum stress. Mol Cell Biol 2005;25:9554e9575. 16. Collins MA, Neafsey EJ, Mukamal KJ, et al. Alcohol in moderation, cardioprotection, and neuroprotection: epidemiological considerations and mechanistic studies. Alcohol Clin Exp Res 2009;33:206e219. 17. Miyamae M, Kaneda K, Domae N, Figueredo VM. Cardioprotection by regular ethanol consumption: potential mechanisms and clinical application. Current Drug Abuse Rev 2010;3:39e48. 18. Miyamae M, Diamond I, Weiner MW, et al. Regular alcohol consumption mimics cardiac preconditioning by protecting against ischemia-reperfusion injury. Proc Nat Acad Sci U S A 1997;94:3235e3239. 19. Di Castelnuovo A, Costanzo S, Donati MB, et al. Prevention of cardiovascular risk by moderate alcohol consumption: epidemiologic evidence and plausible mechanisms. Int Emerg Med 2010;5:291e297.
Invited Commentary James S Allan, Boston, MA
MD, FACS
A plethora of epidemiologic studies has shown that light to moderate consumption of alcoholic beverages substantially reduces the risk of myocardial infarction and stroke, and that this protective effect is most pronounced among those who have other significant risk factors for cardiovascular disease. Moderate alcohol consumption is also known to mitigate certain conditions associated with cardiovascular disease, such as diabetes and hyperlipidemia, and the mechanisms by which these actions occur
Allan
Invited Commentary
1181
have been elucidated in a number of laboratory studies. Although some have argued that moderate alcohol intake is merely the marker of a healthier lifestyle, the weight of the epidemiologic and investigational data suggests that the relationship is more than associative. Dr Sellke and colleagues used a large-animal model of chronic myocardial ischemia to determine at a molecular level whether alcohol exerts a differential effect on proand anti-apoptotic pathways. Two items in the experimental design are worth noting. First, the investigators took advantage of the Yorkshire swine, an experimental model that is far more similar in physiology to human subjects than are murine experimental systems. Second, the investigators used ethanol as the source of alcohol in the experiment. This is significant because there has been some debate in the epidemiologic literature about whether cardioprotection is due to the alcohol itself, or whether this effect is mediated by other associated compounds, such as the naturally occurring phenol, resveratrol, prominent in red wine. The principal finding in this manuscript is that ethanol promotes survival signaling and downregulates both apoptosis and MTOR signaling in both chronically ischemic and normal myocardium. It is known that oxidative stress, particularly if it is chronic and mild, can lead to programmed cell death, and it is likely that the favorable changes in pro-and anti-apoptotic pathways induced by ethanol reduce the number of cells that enter or complete this terminal pathway. What is not clear is whether historical moderate alcohol consumption would have an impact on acute ischemic events, where necrotic cell death (with associated inflammation) predominates. Sellke and associates’ work also raises important mechanistic questions about cellular senescence, and the influence that alcohol consumption might have on longevity. It is generally believed that cellular senescence occurs as a consequence of accumulated DNA damage, typified by telomere shortening, and that apoptosis is the principal mode of senescent cell death. It is conceivable that raising the threshold for a cell to enter apoptotic death could extend a cell’s lifespan, resulting in greater longevity for the organism. Studies of centenarians and supercentenarians consistently report that they enjoy a myriad of “vices,” including daily alcohol consumption. However, it remains unclear as to whether these survivors have longevity because of alcohol, or in spite of alcohol. The answer to this question awaits further research. Whether you have another round while you’re waiting is entirely up to you.
9. Lassaletta AD, Chu LM, Robich MP, et al. Overfed ossabaw swine with early stage metabolic syndrome have normal coronary collateral development in response to chronic ischemia. Basic Res Cardiol 2012;107:243. 10. Whelan RS, Kaplinskiy V, Kitsis RN. Cell death in the pathogenesis of heart disease: mechanisms and significance. Ann Rev Physiol 2010;72:19e44. 11. Perrelli MG, Pagliaro P, Penna C. Ischemia/reperfusion injury and cardioprotective mechanisms: role of mitochondria and reactive oxygen species. World J Cardiol 2011;3: 186e200. 12. Konstantinidis K, Whelan RS, Kitsis RN. Mechanisms of cell death in heart disease. Arterioscleros Thromb Vasc Biol 2012; 32:1552e1562. 13. Lam EW, Francis RE, Petkovic M. Foxo transcription factors: key regulators of cell fate. Biochemic Soc Trans 2006;34: 722e726. 14. Towler MC, Hardie DG. Amp-activated protein kinase in metabolic control and insulin signaling. Circ Res 2007;100: 328e341. 15. Terai K, Hiramoto Y, Masaki M, et al. Amp-activated protein kinase protects cardiomyocytes against hypoxic injury through attenuation of endoplasmic reticulum stress. Mol Cell Biol 2005;25:9554e9575. 16. Collins MA, Neafsey EJ, Mukamal KJ, et al. Alcohol in moderation, cardioprotection, and neuroprotection: epidemiological considerations and mechanistic studies. Alcohol Clin Exp Res 2009;33:206e219. 17. Miyamae M, Kaneda K, Domae N, Figueredo VM. Cardioprotection by regular ethanol consumption: potential mechanisms and clinical application. Current Drug Abuse Rev 2010;3:39e48. 18. Miyamae M, Diamond I, Weiner MW, et al. Regular alcohol consumption mimics cardiac preconditioning by protecting against ischemia-reperfusion injury. Proc Nat Acad Sci U S A 1997;94:3235e3239. 19. Di Castelnuovo A, Costanzo S, Donati MB, et al. Prevention of cardiovascular risk by moderate alcohol consumption: epidemiologic evidence and plausible mechanisms. Int Emerg Med 2010;5:291e297.
Invited Commentary James S Allan, Boston, MA
MD, FACS
A plethora of epidemiologic studies has shown that light to moderate consumption of alcoholic beverages substantially reduces the risk of myocardial infarction and stroke, and that this protective effect is most pronounced among those who have other significant risk factors for cardiovascular disease. Moderate alcohol consumption is also known to mitigate certain conditions associated with cardiovascular disease, such as diabetes and hyperlipidemia, and the mechanisms by which these actions occur
Allan
Invited Commentary
1181
have been elucidated in a number of laboratory studies. Although some have argued that moderate alcohol intake is merely the marker of a healthier lifestyle, the weight of the epidemiologic and investigational data suggests that the relationship is more than associative. Dr Sellke and colleagues used a large-animal model of chronic myocardial ischemia to determine at a molecular level whether alcohol exerts a differential effect on proand anti-apoptotic pathways. Two items in the experimental design are worth noting. First, the investigators took advantage of the Yorkshire swine, an experimental model that is far more similar in physiology to human subjects than are murine experimental systems. Second, the investigators used ethanol as the source of alcohol in the experiment. This is significant because there has been some debate in the epidemiologic literature about whether cardioprotection is due to the alcohol itself, or whether this effect is mediated by other associated compounds, such as the naturally occurring phenol, resveratrol, prominent in red wine. The principal finding in this manuscript is that ethanol promotes survival signaling and downregulates both apoptosis and MTOR signaling in both chronically ischemic and normal myocardium. It is known that oxidative stress, particularly if it is chronic and mild, can lead to programmed cell death, and it is likely that the favorable changes in pro-and anti-apoptotic pathways induced by ethanol reduce the number of cells that enter or complete this terminal pathway. What is not clear is whether historical moderate alcohol consumption would have an impact on acute ischemic events, where necrotic cell death (with associated inflammation) predominates. Sellke and associates’ work also raises important mechanistic questions about cellular senescence, and the influence that alcohol consumption might have on longevity. It is generally believed that cellular senescence occurs as a consequence of accumulated DNA damage, typified by telomere shortening, and that apoptosis is the principal mode of senescent cell death. It is conceivable that raising the threshold for a cell to enter apoptotic death could extend a cell’s lifespan, resulting in greater longevity for the organism. Studies of centenarians and supercentenarians consistently report that they enjoy a myriad of “vices,” including daily alcohol consumption. However, it remains unclear as to whether these survivors have longevity because of alcohol, or in spite of alcohol. The answer to this question awaits further research. Whether you have another round while you’re waiting is entirely up to you.
