Epidemiological studies of the past decades have provided a strong body of evidence that elevated levels of ambient particulate air pollution (PM) are associated with increased cardiovascular and respiratory morbidity and mortality. Exacerbations of ischemic and/or arrhythmic cardiac diseases have been linked to PM exposure. At a workshop held at the GSF- National Center for Environment and Health in November 2003, relevant epidemiological and toxicological data of the past 5 years were compiled and potential biological pathways discussed. Available clinical and experimental evidence lends support to the following mechanisms mediating cardiovascular effects of inhaled ambient particles: (i) pulmonary and/or systemic inflammatory responses inducing endothelial dysfunction, a pro-coagulatory state and promotion of atherosclerotic lesions, (ii) dysfunction of the autonomic nervous system in response to direct reflexes from receptors in the lungs and/or to local or systemic inflammatory stimuli, and (iii) cardiac malfunction due to ischemic responses in the myocardium and/or altered ion-channel functions in myocardial cells. While an increasing number of studies addressing these questions support the notion that PM exposure is associated with cardiovascular effects, these studies at present provide only a fragmentary and at times inconclusive picture of the complex biological pathways involved. The available data are consistent with the occurrence of a systemic inflammatory response and an alteration of autonomic cardiac control, but evidence on endothelial dysfunction, pro-coagulatory states, and PM-related myocardial malfunction is as yet scarce. Further studies are therefore needed to substantiate our current understanding of the pathophysiological links between PM exposure and adverse cardiovascular outcomes.

BackgroundThe alterations of subbasal nerve plexus (SBP) innervation and corneal sensation were estimated non-invasively and compared with the values in healthy volunteers. Additionally, this study addressed the relation of SBP changes to the retinal status, glycemic control and diabetes duration.Methodology/Principal FindingsEighteen eyes of diabetic patients with peripheral diabetic neuropathy aged 68.8±8.8 years and twenty eyes of healthy volunteers aged 66.3±13.3 yrs. were investigated with in vivo confocal laser-scanning microscopy (CLSM). An adapted algorithm for image analysis was used to quantify the morphological and topological properties of SBP. These properties were correlated to incidence of diabetic retinopathy (DR) and corneal sensation (Cochet-Bonnet esthesiometer). The developed algorithm allows a fully automated analysis of pre-segmented SBP structures. Altogether, 10 parameters were analysed, and all of them revealed significant differences between diabetic patients and healthy volunteers. The nerve fibre density, total fibre length and nerve branches were found to be significantly lower in patients with diabetes than those of control subjects (nerve fibre density 0.006±0.002 vs. 0.020±0.007 mm/mm2; total fibre length 6223±2419 vs. 19961±6553 µm; nerve branches 25.3±28.6 vs. 141.9±85.7 in healthy volunteers). Also the corneal sensation was significantly lower in diabetic group when compared to controls (43±11 vs. 59±18 mm). There was found no difference in SBP morphology or corneal sensation in the subgroups with (DR) or without (NDR) diabetic retinopathy.Conclusions/SignificanceSBP parameters were significantly reduced in diabetic patients, compared to control group. Interestingly, the SBP impairment could be shown even in the diabetic patients without DR. Although automatic adapted image analysis simplifies the evaluation of in vivo CLSM data, image acquisition and quantitative analysis should be optimised for the everyday clinical practice.

Based on epidemiologic observations, the issue of adverse health effects of inhaled ultrafine particles (UFP) is currently under intensive discussion. We therefore examined cardiovascular effects of UFP in a controlled animal exposure on young, healthy WKY rats. Short-term exposure (24 h) to carbon UFPs (38 nm, 180 microg m (-3)), generated by spark discharging, induced a mild but consistent increase in heart rate (18 bpm, 4.8%), which was associated with a significant decrease in heart-rate variability during particle inhalation. The timing and the transient character of these responses point to a particle induced alteration of cardiac autonomic balance, mediated by a pulmonary receptor activation. After 24 h of inhalation exposure, bronchoalveolar lavage revealed significant but low-grade pulmonary inflammation (clean air 1.9% vs. UFPs 6.9% polymorphonuclear cells) and on histopathology sporadic accumulation of particle-laden macrophages was found in the alveolar region. There was no evidence of an inflammation-mediated increase in blood coagulability, as UFP inhalation did not induce any significant changes in plasma fibrinogen or factor VIIa levels and there were no prothrombotic changes in the lung or the heart at both the protein and mRNA level. Histological analysis revealed no signs of cardiac inflammation or cardiomyopathy. This study therefore provides toxicological evidence for UFP-associated pulmonary and cardiac effects in healthy rats. Our findings suggest that the observed changes are mediated by an altered sympatho-vagal balance in response to UFP inhalation, but do not support the concept of an inflammation-mediated prothrombotic state by UFP.

To compare the reperfusion potential of intravenous anisoy-lated plasminogen streptokinase activator complex (APSAC) a new thrombolytic, and standard therapy with intracoronary streptokinase in acute myocardial infarction (AMI), a randomized multicenter reperfusion trial was performed. Consenting patients with clinical signs of AMI and documented coronary occlusion (flow grade 0 or 1) were randomized to treatment within 6 hours of symptoms (mean, 3.4h) with intravenous APSAC (30 U in 2-4 min) or intracoronary streptokinase (bolus, then 2,000 U/min x 60 min). Reperfusion success was defined as grade 2 or 3 flow at 60 min for intracoronary and 90 min for intravenous therapy. A total of 189 patients (pt) were randomized and 179 pt were evaluable for efficacy. Reperfusion was similar for the two treatments: 52% (49/94) for APSAC and 61% (52/85) for streptokinase (p≤0.2). Success was dependent on initial occlusion grade (p≤0.001): 49% (65/133) for grade 0 (APSAC= 45%, streptokinase=54%), but 78% for grade 1 (APSAC=80%, strepto-kinase=77%). The success of intravenous (APSAC) therapy was also dependent on time to treatment: 59% for ≤4h, versus 36% after 4h (p<0.04). APSAC was well tolerated, the change in mean blood pressure after bolus injection being modest (−11 mmHg). Systemic fibrinolysis was somewhat greater after APSAC than low dose streptokinase: fibrinogen levels averaged 39 ± 4% (SE) of control at 90 minutes after APSAC, versus 64 ± 5% after streptokinase (p<0.01) in the subgroup tested. The rate of bleeding complications was acceptable for both regimens, and other adverse reactions were comparable. Rates of early occlusion were low in both treatment groups, and evolution of ECG and enzymatic indicators were similar. Thus, APSAC provides approximately similar reperfusion results as intracoronary streptokinase, especially when given within 4h, but is easier to administer and is well tolerated.