We evaluated the correlates of baroreflex sensitivity (BRS) in healthy subjects. The study consisted of 117 healthy, normal-weight, nonsmoking male and female subjects aged 23-77 yr. Baroreflex control of heart rate was measured by using the phenylephrine bolus-injection technique. Frequency- and time-domain analysis of heart rate variability and an exercise test were performed. Plasma norepinephrine, epinephrine, insulin, and arginine vasopressin concentrations and plasma renin activity were measured. In the univariate analysis, BRS correlated with age (r = -0.65, P < 0.001), diastolic blood pressure (r = -0.47, P < 0.001), exercise capacity (r = 0.60, P < 0.001), and the high-frequency component of heart rate variability (r = 0.64, P < 0.001). There was also a significant correlation between BRS and plasma norepinephrine concentration (r = -0.22, P < 0.05) and plasma renin activity (r = 0.32, P < 0.001). According to the multivariate analysis, age and gender were the most important physiological correlates of BRS. They accounted for 52% of interindividual BRS variation. In addition, diastolic blood pressure and high-frequency component of heart rate variability were significant independent correlates of BRS. BRS was significantly higher in men than in women (15.0 +/- 1.2 vs. 10.2 +/- 1.1 ms/mmHg, respectively; P < 0.01). Twenty-four percent of women > 40 yr old and 18% of men > 60 yr old had markedly depressed BRS (< 3 ms/mmHg). We conclude that physiological factors, particularly age and gender, have significant impact on BRS in healthy subjects. In addition, we demonstrate that BRS values that have been proposed to be useful in identifying postinfarction patients at high risk of sudden death are frequently found in healthy subjects.

Background-Daily variations in ambient particulate air pollution have been associated with cardiovascular mortality and morbidity. We therefore assessed the associations between levels of the 3 main modes of urban aerosol distribution and the occurrence of ST-segment depressions during repeated exercise tests. Methods and Results-Repeated biweekly submaximal exercise tests were performed during 6 months among adult subjects with stable coronary heart disease in Helsinki, Finland. Seventy-two exercise-induced ST-segment depressions Ͼ0.1 mV occurred during 342 exercise tests among 45 subjects. Simultaneously, particle mass Ͻ2.5 m (PM2.5) and the number concentrations of ultrafine particles (particle diameter 10 to 100 nm [NC 0.01-0.1 ]) and accumulation mode particles (100 to 1000 nm [NC 0.1-1 ]) were monitored at a central site. Levels of particulate air pollution 2 days before the clinic visit were significantly associated with increased risk of ST-segment depression during exercise test. The association was most consistent for measures of particles reflecting accumulation mode particles (odds ratio 3.29; 95% CI, 1.57 to 6.92 for NC 0.1-1 and 2.84; 95% CI, 1.42 to 5.66 for PM2.5), but ultrafine particles also had an effect (odds ratio 3.14; 95% CI, 1.56 to 6.32), which was independent of PM2.5. Also, gaseous pollutants NO 2 and CO were associated with an increased risk for ST-segment depressions. No consistent association was observed for coarse particles. The associations tended to be stronger among subjects who did not use ␤-blockers. Conclusions-The present results suggest that the effect of particulate air pollution on cardiovascular morbidity is at least partly mediated through increased susceptibility to myocardial ischemia. (Circulation. 2002;106:933-938.)

Background-Detailed metabolic defects in glucose and energy metabolism and abnormalities in a variety of cardiovascular risk factors are largely unknown in subjects with the metabolic syndrome. Methods and Results-We characterized the metabolic syndrome in 119 nondiabetic offspring of diabetic probands.Cardiovascular risk factors, including cytokines and adhesion molecules, were measured. Insulin sensitivity was assessed by the euglycemic hyperinsulinemic clamp and indirect calorimetry; intra-abdominal fat and subcutaneous fat were assessed by CT; and maximal oxygen consumption was measured with a bicycle ergometer test. By applying factor analysis, we identified a single factor, the metabolic syndrome factor, from the following variables: 2-hour glucose, fasting insulin, body mass index, waist, HDL cholesterol, triglycerides, and mean blood pressure. Subjects with the highest factor score were defined as having the metabolic syndrome. During hyperinsulinemia, the highest factor score was associated with decreased rates of glucose oxidation and nonoxidative glucose disposal, high rates of lipid oxidation, low energy expenditure, and impaired suppression of free fatty acids during hyperinsulinemia. Furthermore, the metabolic syndrome was associated with a high amount of visceral fat, hypoadiponectinemia, a low maximum oxygen uptake, and high levels of C-reactive protein, proinflammatory cytokines, and adhesion molecules. Conclusions-The metabolic syndrome is characterized by an excess of intra-abdominal fat, hypoadiponectinemia, insulin resistance in skeletal muscle and adipose tissue, multiple defects in glucose and energy metabolism, and elevated levels of cytokines and adhesion molecules.

No studies are available that have compared early defects in glucose metabolism in the offspring of insulin-deficient and insulin-resistant probands with non-insulin-dependent diabetes mellitus (NIDDM). To investigate this issue, we evaluated insulin secretion capacity with oral and intravenous glucose tolerance tests and with the hyperglycemic clamp, and insulin action with the euglycemic insulin clamp in 20 offspring of NIDDM patients with low fasting C-peptide (+/-450 pmol/liter), reflecting deficient insulin secretion (IS-group), 18 offspring of NIDDM patients with high fasting C-peptide (>/= 880 pmol/liter), reflecting insulin resistance (IR-group), and 14 healthy control subjects without a family history of NIDDM. The frequency of impaired glucose tolerance was 45.0% in the IS-group and 50% in the IR-group. The IS-group had lower insulin-glucose response at 30 min in the oral glucose tolerance test (85.2+/-10.0 pmol insulin per mmol glucose) than the control group (136.4+/-23.1 pmol insulin per mmol glucose; P < 0.05) and the IR-group (115.6+/-11.8 pmol insulin per mmol glucose; P = 0.05). Furthermore, the acute insulin response during the first 10 min of an intravenous glucose tolerance test was lower in the IS-group than in the IR-group. Maximal insulin secretion capacity evaluated by C-peptide levels during the hyperglycemic clamp did not differ between the groups. The IR-group had lower rates of whole body glucose uptake (60.1+/-4.6 micromol per lean body mass per minute) than did the control group (84.2+/-5.0 micromol per lean body mass per minute; P < 0.001) or the IS-group (82.6+/-5.9 micromol per lean body mass per minute; P < 0.01) and this was due to reduced glucose nonoxidation. To conclude, both impaired insulin secretion and insulin action seem to be inherited and could represent the primary defects in glucose metabolism in the offspring of NIDDM probands.

Previous studies have shown an association between elevated concentrations of particulate air pollution and cardiovascular morbidity and mortality. Therefore, the association between daily variation of ultrafine and fine particulate air pollution and cardiac autonomic control measured as heart rate variability (HRV) was studied in a large multicenter study in Amsterdam, the Netherlands, Erfurt, Germany, and Helsinki, Finland. Elderly subjects (n=37 in Amsterdam, n=47 in both Erfurt and Helsinki) with stable coronary artery disease were followed for 6 months with biweekly clinical visits. During the visits, ambulatory electrocardiogram was recorded during a standardized protocol including a 5-min period of paced breathing. Time and frequency domain analyses of HRV were performed. A statistical model was built for each center separately. The mean 24-h particle number concentration (NC) (1,000/cm(3)) of ultrafine particles (diameter 0.01-0.1 microm) was 17.3 in Amsterdam, 21.1 in Erfurt, and 17.0 in Helsinki. The corresponding values for PM2.5 were 20.0, 23.1, and 12.7 microg/m(3). During paced breathing, ultrafine particles, NO(2), and CO were at lags of 0-2 days consistently and significantly associated with decreased low-to-high frequency ratio (LF/HF), a measure of sympathovagal balance. In a pooled analysis across the centers, LF/HF decreased by 13.5% (95% confidence interval: -20.1%, -7.0%) for each 10,000/cm(3) increase in the NC of ultrafine particles (2-day lag). PM2.5 was associated with reduced HF and increased LF/HF in Helsinki, whereas the opposite was true in Erfurt, and in Amsterdam, there were no clear associations between PM2.5 and HRV. The results suggest that the cardiovascular effects of ambient ultrafine and PM2.5 can differ from each other and that their effect may be modified by the characteristics of the exposed subjects and the sources of PM2.5.

Background and Purpose-More effective imaging methods are needed to overcome the limitations of CT in the investigation of treatments for acute ischemic stroke. Diffusion-weighted MRI (DWI) is sensitive in detecting infarcted brain tissue, whereas perfusion-weighted MRI (PWI) can detect brain perfusion in the same imaging session. Combining these methods may help in identifying the ischemic penumbra, which is an important concept in the hemodynamics of acute stroke. The purpose of this study was to determine whether combined DWI and PWI in acute (Ͻ24 hours) ischemic stroke can predict infarct growth and final size. Methods-Forty-six patients with acute ischemic stroke underwent DWI and PWI on days 1, 2, and 8. No patient received thrombolysis. Twenty-three patients underwent single-photon emission CT in the acute phase. Lesion volumes were measured from DWI, SPECT, and maps of relative cerebral blood flow calculated from PWI. Results-The mean volume of infarcted tissue detected by DWI increased from 46.1 to 75.6 cm 3 between days 1 and 2 (PϽ0.001; nϭ46) and to 78.5 cm 3 after 1 week (PϽ0.001; nϭ42). The perfusion-diffusion mismatch correlated with infarct growth (rϭ0.699, PϽ0.001).

Background— Catheter-based intracoronary vascular endothelial growth factor (VEGF) gene transfer is a potential treatment for coronary heart disease. However, only limited data are available about local VEGF gene transfer given during angioplasty (PTCA) and stenting. Methods and Results— Patients with coronary heart disease (n=103; Canadian Cardiovascular Society class II to III; mean age, 58±6 years) were recruited in this randomized, placebo-controlled, double-blind phase II study. PTCA was performed with standard methods, followed by gene transfer with a perfusion-infusion catheter. Ninety percent of the patients were given stents; 37 patients received VEGF adenovirus (VEGF-Adv, 2×10 10 pfu), 28 patients received VEGF plasmid liposome (VEGF-P/L; 2000 μg of DNA with 2000 μL of DOTMA:DOPE [1:1 wt/wt]), and 38 control patients received Ringer’s lactate. Follow-up time was 6 months. Gene transfer to coronary arteries was feasible and well tolerated. The overall clinical restenosis rate was 6%. In quantitative coronary angiography analysis, the minimal lumen diameter and percent of diameter stenosis did not significantly differ between the study groups. However, myocardial perfusion showed a significant improvement in the VEGF-Adv-treated patients after the 6-month follow-up. Some inflammatory responses were transiently present in the VEGF-Adv group, but no increases were detected in the incidences of serious adverse events in any of the study groups. Conclusions— Gene transfer with VEGF-Adv or VEGF-P/L during PTCA and stenting shows that (1) intracoronary gene transfer can be performed safely (no major gene transfer-related adverse effects were detected), (2) no differences in clinical restenosis rate or minimal lumen diameter were present after the 6-month follow-up, and (3) a significant increase was detected in myocardial perfusion in the VEGF-Adv-treated patients.

Summary. The aim of this study was to assess the effects of a 1-year intensified diet and exercise education regimen on habitual physical activity and aerobic capacity in middle-aged, obese patients with newly-diagnosed Type 2 (non-insulin-dependent) diabetes mellitus. In addition, we analysed whether the level and the changes in physical activity and aerobic capacity are related to the metabolic control of diabetes. After a 3-month basic education programme, 78 patients (45 men, 33 women) were randomly placed in an intervention or conventionally treated group. The intervention group received intensified diet education and continuous encouragement to increase physical activity which was monitored using exercise records and questionnaires. Aerobic capacity was assessed by measuring oxygen uptake at anaerobic threshold and at peak exercise. The proportion of patients with regular recreational exercise increased from 24 % to 38 % in the intervention men (0.10 < p < 0.20), remained at 54 % in the conventionally treated men, increased from 53 % to 70% in the intervention women (0.10 < p < 0.20) and from 31% to 50 % (0.10