Asymmetric dimethylarginine as an independent risk marker for mortality in ambulatory patients with peripheral arterial disease.

BACKGROUND: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthesis causing endothelial dysfunction, an early sign of atherogenesis. Symmetric dimethylarginine (SDMA) does not inhibit NO synthases. Peripheral arterial disease (PAD) is a systemic indication of atherosclerosis. METHODS: We assessed the associations between both ADMA and SDMA blood levels and major cardiovascular and cerebrovascular events or death from any cause within a 5-year follow-up in the multicentre getABI trial. From a cohort of 6821 primary care patients, aged ≥65 years, all 1260 patients with prevalent PAD were compared with a random sample of 1187 non-PAD controls. A total of 11,544 patient-years were documented. Multivariate risks were calculated by Cox proportional hazard models, adjusting for PAD, renal dysfunction and other important cardiovascular risk factors. RESULTS: We documented 390 deaths, 296 cardiovascular events and 98 cerebrovascular events. Increased ADMA levels in the 4th quartile were significantly associated with total mortality [hazard ratio (HR) 1.41; 95% CI 1.14-1.74] and with cardiovascular events (HR 1.32; 95% CI 1.03-1.69), but there was a nonsignificant association with cerebrovascular events (HR 1.50; 95% CI 0.98-2.29). Increased SDMA was only just significantly associated with mortality (HR 1.27; 95% CI 1.01-1.59). In PAD patients compared with non-PAD controls, only mean SDMA concentration was considerably increased (0.52 µmol L(-1) vs. 0.48 µmol L(-1); P < 0.001) mainly because of a highly significant association with impaired renal function. CONCLUSION: These data suggest that ADMA but not SDMA is an independent risk marker for death from any cause or from cardiovascular events. The association between SDMA and mortality is in part explained by a close link between SDMA and renal function.

One-year safety and quality of life outcomes in patients with atrial fibrillation on dronedarone: prospective, non-interventional study in German ambulatory care.

BACKGROUND AND AIMS: The multichannel blocker dronedarone is currently indicated for the maintenance of sinus rhythm after successful cardioversion in adult clinically stable patients with paroxysmal or persistent atrial fibrillation (AF), with careful monitoring of cardiac, hepatic and renal function. We aimed to investigate patients' quality of life (QoL) and tolerability and effectiveness of dronedarone under real life conditions. METHODS: In the 1-year prospective, non-interventional IMPULS study, 161 office-based cardiologists, general practitioners and internists throughout Germany documented 549 patients with AF who were currently or newly prescribed dronedarone (safety set, SS). Of those, 342 patients (full analysis set, FAS) provided data on QoL at baseline, 6 months and 12 months). RESULTS: Mean age of patients was 67.6/66.3 years; 53.0 %/57.3 % were men (SS/FAS). AF type at inclusion in the SS/FAS was paroxysmal in 71.9 %/71.3 % and persistent in 26.0 %/26.6 % (missing in 2.0 %/2.0 %). The proportion of patients in sinus rhythm increased from 44.6 % at baseline to 70.2 % (SS). The mean value on the 100-point visual analogue scale (EuroQol EQ-5D) increased from 62.3 ± 17.1 at baseline by 11.4 ± 18.7 points (FAS, p<0.0001). The AF-QoL Psychological Domain improved from 44.6 ± 22.6 at baseline by 16.0 ± 23.5 points at 1 year (p<0.0001), the AF-QoL physical domain from 49.5 ± 22.1 by 10.9 ± 22.5 points (p<0.0001), and the AF-QoL sexual domain from 61.8 ± 27.1 by 6.6 ± 28.2 points (p<0.0001). In all, 136 patients (24.8 % of all patients in the safety set) had at least one adverse drug reaction (ADR) causally related to dronedarone. CONCLUSIONS: Various dimensions of quality of life of patients with AF were improved on dronedarone under clinical practice conditions. No previously unknown safety issues were noted.

High prevalence of peripheral arterial disease and low treatment rates in elderly primary care patients with diabetes.

Representative data on peripheral arterial disease (PAD) in community-based office practice are scarce while at the same time of high interest. Thus, we aimed to determine the prevalence of peripheral arterial disease (PAD), comorbidity of atherothrombotic manifestations, and treatment intensity among elderly diabetic patients in primary care. In this monitored cross-sectional study, 344 general practitioners throughout Germany determined the ankle-brachial index (ABI) of 6880 consecutive, unselected patients aged 65 years or older with bilateral Doppler ultrasound measurements. PAD was defined according to the recent American Heart Association guidelines (using the higher of the 2 systolic ankle pressures: ABI < 0.9) or peripheral revascularisation, or amputation because of PAD. Coronary events (CAD) and cerebrovascular events (CVD) were taken from the patient's history without additional diagnostic measures. Diabetes was defined according to the clinical diagnosis of the physician and/or HbA1c > or = 6.5 % and/or intake of oral antidiabetic medication and/or application of insulin. 1.743 patients were classified as diabetics: the median disease duration was 6 years (1st; 3rd quartile: 2; 11), median HbA1c 6.6 % (5.9; 7.3), mean age 72.5 +/- 5.4 years, and 51.4 % were females. Diabetics had in comparison with non-diabetics a higher prevalence of PAD defined as ABI < 0.9 (26.3 % vs. 15.3 %, univariate odds ratio 2.0 [95 % confidence interval: 1.7; 2.3]), intermittent claudication (5.1 % vs. 2.1 %, OR: 2.5 [1.9; 3.4]), known CAD (16.1 % vs. 10.6 %, OR: 1.6 [1.4; 1.9]), and known CVD (6.8 % vs. 4.8 %; OR: 1.4 [1.2; 1.8]). 57.4 % of the diabetics with previously known PAD (as only atherothrombotic manifestation) received antiplatelet therapy (vs. 75.1 % with CAD and/or CVD only). The ABI was suitable as screening measure in the primary care setting. In elderly diabetics in comparison to non-diabetics, the prevalence of PAD was very high. Despite the known benefits of antiplatelet therapy, PAD patients were less intensively treated than patients with CAD or CVD.

Combined treatment of rat rhabdomyosarcoma R1H with mitomycin C and X-rays.

The effects of mitomycin C (MTC) alone and in combination with radiation on R1H rhabdomyosarcomas in WAG/Rij rats were studied. Growth delay was determined from tumor volume growth curves and proportion of tumor and host cells from flow cytometry measurements. Only minor growth delays were obtained with MTC at doses near the toxic level while irradiation applied in three fractions of 10 Gy in three weeks yielded growth delays of 27, 44, and 51 days measured at volumes of 2, 5, and 10 cm3, respectively. The combination of 1 micrograms/kg b.w. MTC and 10 Gy irradiation given in three weekly fractions resulted in 21, 28, and 29 days growth delay for the above tumor volumes. The lower effect of combination as compared to irradiation alone is discussed with the flow cytometry data. These data show that early after start of treatment the proportion of tumor cells remains constant in contrast to radiation alone where the fraction of tumor cells decreases because of influx of granulocytes and macrophages into the tumor. In contrast to the reduced effect on tumors the combination treatment was considerably more toxic for the animals than the single treatments.