Angiotensin II favors progression to heart failure in diabetic hearts: role of myocardial fatty acid oxidation downregulation

Purpose: Diabetic myocardium is particularly vulnerable to develop heart failure in response to chronic stress conditions including hypertension or myocardial infarction. We have recently observed that angiotensin II (Ang II)-mediated downregulation of the fatty acid oxidation pathway favors occurrence of heart failure by myocardial accumulation of lipids (lipotoxicity). Because diabetic heart is exposed to high levels of circulating fatty acid, we determined whether insulin resistance favors development of heart failure in mice with Ang II-mediated myocardial remodeling.Methods: To study the combined effect of diabetes and Ang II-induced heart remodeling, we generated leptin-deficient/insulin resistant (Lepob/ob) mice with cardiac targeted overexpression of angiotensinogen (TGAOGN). Left ventricular (LV) failure was indicated by pulmonary congestion (lung weight/tibial length>+2SD of wild-type mice). Myocardial metabolism and function were assessed during in vitro isolated working heart perfusion.Results: Forty-eight percent of TGAOGN mice without insulin resistance exhibited pulmonary congestion at the age of 6 months associated with increased myocardial BNP expression (+375% compared with WT) and reduced LV power (developed pressure x cardiac output; -15%). The proportion of mice presenting heart failure was markedly increased to 71% in TGAOGN mice with insulin resistance (TGAOGN/Lepob/ob). TGAOGN/Lepob/ob mice with heart failure exhibited further increase of BNP compared with failing non-diabetic TGAOGN mice (+146%) and further reduction of cardiac power (-59%). Mice with insulin resistance alone (Lepob/ob) did not exhibit signs of heart failure or LV dysfunction. Myocardial fatty acid oxidation measured during in vitro perfusion was markedly increased in non-failing hearts from Lepob/ob mice (+380% compared with WT) and glucose oxidation decreased (-72%). In contrast, fatty acid and glucose oxidation did not differ from Lepob/ob mice in hearts from TGAOGN/Lepob/ob mice without heart failure. However, both fatty acid and glucose oxidation were markedly decreased (-47% and -48%, respectively, compared with WT/Lepob/+) in failing hearts from TGAOGN/Lepob/ob mice. Reduction of fatty acid oxidation was associated with marked reduction of protein expression of a number of regulatory enzymes implied in fatty acid oxidation.Conclusions: Insulin resistance favors the progression to heart failure during chronic exposure of the myocardium to Ang II. Our results are compatible with a role of Ang II-mediated downregulation of fatty acid oxidation, potentially promoting lipotoxicity.

Institutional legacies, employment and professional integration of non EU/EEA doctors in France

Internationally, policies for attracting highly-skilled migrants have become the guidelines mainly used by the Organisation for Economic Co-operation and Development (OECD) countries. Governments are implementing specific procedures to capture and facilitate their mobility. However, all professions are not equal when it comes to welcoming highly-skilled migrants. The medical profession, as a protective market, is one of these. Taking the case of non-EU/EEA doctors in France, this paper shows that the medical profession defined as the closed labour market, remains the most controversial in terms of professional integration of migrants, protectionist barriers to migrant competition and challenge of medical shortage. Based on the path-dependency approach, this paper argues that non-EU/EEA doctors' issues in France derive from a complex historical process of interaction between standards settled in the past, particularly the historical power of medical corporatism, the unexpected long-term effects of French hospital reforms of 1958, and budgetary pressures. Theoretically, this paper shows two significant findings. Firstly, the French medical system has undergone a series of transformations unthinkable in the strict sense of a path-dependence approach: an opening of the medical profession to foreign physicians in the context of the Europeanisation of public policy, acceptance of non-EU/EEA doctors in a context of medical shortage and budgetary pressures. Secondly, there is no change of the overall paradigm: significantly, the recruitment policies of non-EU/EEA doctors continue to highlight the imprint of the past and reveal a significant persistence of prejudices. Non-EU/EEA doctors are not considered legitimate doctors even if they have the qualifications of physicians which are legitimate in their country and which can be recognised in other receiving countries.