Human CYP2J2 is abundant in heart and active in the biosynthesis of epoxyeicosatrienoic acids (EETs); however, the functional role of this P450 and its eicosanoid products in the heart remains unknown. Transgenic mice with cardiomyocyte-specific overexpression of CYP2J2 were generated. CYP2J2 transgenic (Tr) mice have normal heart anatomy and basal contractile function. CYP2J2 Tr hearts have improved recovery of left ventricular developed pressure (LVDP) compared with wild-type (WT) hearts after 20 minutes ischemia and 40 minutes reperfusion. Perfusion with the selective P450 epoxygenase inhibitor N-methylsulphonyl-6-(2-proparglyloxyphenyl)hexanamide (MS-PPOH) for 20 minutes before ischemia results in reduced postischemic LVDP recovery in WT hearts and abolishes the improved postischemic LVDP recovery in CYP2J2 Tr hearts. Perfusion with the ATP-sensitive K(+) channel (K(ATP)) inhibitor glibenclamide (GLIB) or the mitochondrial K(ATP) (mitoK(ATP)) inhibitor 5-hydroxydecanoate (5-HD) for 20 minutes before ischemia abolishes the cardioprotective effects of CYP2J2 overexpression. Flavoprotein fluorescence, a marker of mitoK(ATP) activity, is higher in cardiomyocytes from CYP2J2 Tr versus WT mice. Moreover, CYP2J2-derived EETs (1 to 5 micromol/L) increase flavoprotein fluorescence in WT cardiomyocytes. CYP2J2 Tr mice exhibit increased expression of phospho-p42/p44 mitogen-activated protein kinase (MAPK) after ischemia, and addition of the p42/p44 MAPK kinase (MEK) inhibitor PD98059 during reperfusion abolishes the cardioprotective effects of CYP2J2 overexpression. Together, these data suggest that CYP2J2-derived metabolites are cardioprotective after ischemia, and the mechanism for this cardioprotection involves activation of mitoK(ATP) and p42/p44 MAPK.
Intensive care is a substantial financial burden on the US health care system, with spending on critical illness exceeding $80 billion per year, approximately 3% of all health care spending and nearly 1% of the gross domestic product. 1 In contrast, the United Kingdom spends only 0.1% of its gross domestic product on critical care services, with no evidence of worse patient outcomes and similar life expectancies as in the United States. 2 Although there are many differences between these 2 countries, one significant difference is intensive care unit (ICU) bed supply. The United States has 25 ICU beds per 100 000 people, as compared with 5 per 100 000 in the United Kingdom. 3 As a result, ICU case-mix differs substantially. In the United Kingdom, the majority of ICU patients are at high risk for death, whereas in the United States, many patients are admitted to the ICU for observation. 4 At the same time, compared with patients in the United Kingdom, substantially more patients in the United States die in the ICU, suggesting that increased bed availability appears to reduce the incentive to keep dying patients out of the ICU. 4 The apparent influence of ICU bed supply on ICU bed utilization brings forward the concern of demand elasticity in the ICU, the notion that ICU beds create their own demand. 5 In classical economics, demand elasticity measures how much the demand for a good or service changes in response to changes in another related factor. Demand elasticity is usually considered in terms of price; as price decreases, demand increases. However, it also is relevant to think of demand elasticity in terms of the supply of the good or service. Just as the creation of a new lane on the interstate highway can lead to increased traffic as new drivers seize the opportunity to travel on the larger road, 6 new critical care beds can lead to increased use. As supply constraints are removed, clinicians are more likely to use the service, even for patients unlikely to benefit.Under a model of demand elasticity, the case mix of patients admitted to the ICU might change depending on bed availability (Figure). Ideally the target population for ICU admission would be those patients who are critically ill and have the greatest probability of benefiting from ICU care. In the setting of demand elasticity, with increased ICU bed supply, there would be more ICU admissions for patients unlikely to benefit, including those who are not as critically ill and those who are critically ill but unlikely to survive regardless of ICU care. These patients might more appropriately receive care elsewhere. The reverse would be true in settings of low ICU bed supply because there would be greater incentive to keep these patients out of the ICU.Most practicing intensivists observe the effects of ICU demand elasticity every day. When the physician is
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