AimsPatients with paroxysmal atrial fibrillation (AF) often present with typical angina pectoris and mildly elevated levels of cardiac troponin (non ST-segment elevation myocardial infarction) during an arrhythmic event. However, in a large proportion of these patients, significant coronary artery disease is excluded by coronary angiography. Here we explored the potential underlying mechanism of these events.Methods and resultsA total of 14 pigs were studied using a closed chest, rapid atrial pacing (RAP) model. In five pigs RAP was performed for 7 h (600 b.p.m.; n = 5), in five animals RAP was performed in the presence of angiotensin-II type-1-receptor (AT1-receptor) inhibitor irbesartan (RAP+Irb), and four pigs were instrumented without intervention (Sham). One-factor analysis of variance was performed to assess differences between and within the three groups. Simultaneous measurements of fractional flow reserve (FFR) and coronary flow reserve (CFR) before, during, and after RAP demonstrated unchanged FFR (P = 0.327), but decreased CFR during RAP (RAP: 67.7 ± 7.2%, sham: 97.2 ± 2.8%, RAP+Irb: 93.2 ± 3.3; P = 0.0013) indicating abnormal left ventricular (LV) microcirculation. Alterations in microcirculatory blood flow were accompanied by elevated ventricular expression of NADPH oxidase subunit Nox2 (P = 0.039), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1, P = 0.004), and F2-isoprostane levels (P = 0.008) suggesting RAP-related oxidative stress. Plasma concentrations of cardiac troponin-I (cTn-I) increased in RAP (RAP: 613.3 ± 125.8 pmol/L vs. sham: 82.5 ± 12.5 pmol/L; P = 0.013), whereas protein levels of eNOS and LV function remained unchanged. RAP+Irb prevented the increase of Nox2, LOX-1, and F2-isoprostanes, and abolished the impairment of microvascular blood flow.ConclusionRapid atrial pacing induces AT1-receptor-mediated oxidative stress in LV myocardium that is accompanied by impaired microvascular blood flow and cTn-I release. These findings provide a plausible mechanism for the frequently observed cTn-I elevation accompanied with typical angina pectoris symptoms in patients with paroxysmal AF and normal (non-stenotic) coronary arteries.

Erythropoiesis must be tightly balanced to guarantee adequate oxygen delivery to all tissues in the body. This process relies predominantly on the hormone erythropoietin (EPO) and its transcription factor hypoxia inducible factor (HIF). Accumulating evidence suggests that oxygen-sensitive prolyl hydroxylases (PHDs) are important regulators of this entire system. Here, we describe a novel mouse line with conditional PHD2 inactivation (cKO P2) in renal EPO producing cells, neurons, and astrocytes that displayed excessive erythrocytosis because of severe overproduction of EPO, exclusively driven by HIF-2␣. In contrast, HIF-1␣ served as a protective factor, ensuring survival of cKO P2 mice with HCT values up to 86%. Using different genetic approaches, we show that simultaneous inactivation of PHD2 and HIF-1␣ resulted in a drastic PHD3 reduction with consequent overexpression of HIF-2␣-related genes, neurodegeneration, and lethality. Taken together, our results demonstrate for the first time that conditional loss of PHD2 in mice leads to HIF-2␣-dependent erythrocytosis, whereas HIF-1␣ protects these mice, providing a platform for developing new treatments of EPO-related disorders, such as anemia. (Blood.

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OBJECTIVE—The aim of this study was to evaluate the Saxon Diabetes Management Program (SDMP), which is based on integrated practice guidelines, shared care, and integrated quality management. The SDMP was implemented into diabetes contracts between health insurance providers, general practitioners (GPs), and diabetes specialized practitioners (DSPs) unified in the Saxon association of Statutory Health Insurance Physicians. RESEARCH DESIGN AND METHODS—The evaluation of the SDMP in Germany represents a real-world study by using clinical data collected from participating physicians. Between 2000 and 2002 all DSPs and about 75% of the GPs in Saxony participated. Finally, 291,771 patients were included in the SDMP. Cross-sectional data were evaluated at the beginning of 2000 (group A1) and at the end of 2002 (group A2). A subcohort of 105,204 patients was followed over a period of 3 years (group B). RESULTS—The statewide implementation of the SDMP resulted in a change in therapeutic practice and in better cooperation. The median A1C at the time of referral to DSPs decreased from 8.5 to 7.5%, and so did the overall mean. At the end, 78 and 61% of group B achieved the targets for A1C and blood pressure, respectively, recommended by the guidelines compared with 69 and 50% at baseline. Patients with poorly controlled diabetes benefited the most. Preexisting regional differences were aligned. CONCLUSIONS—Integrated care disease management with practicable integrated quality management including collaboration between GPs and specialist services is a significant innovation in chronic care management and an efficient way to improve diabetes care continuously.

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