Different alterations in the insulin-stimulated glucose uptake in the athlete's heart and skeletal muscle.

Physical training increases skeletal muscle insulin sensitivity. Since training also causes functional and structural changes in the myocardium, we compared glucose uptake rates in the heart and skeletal muscles of trained and untrained individuals. Seven male endurance athletes (VO2max 72 +/- 2 ml/kg/min) and seven sedentary subjects matched for characteristics other than VO2max (43 +/- 2 ml/kg/min) were studied. Whole body glucose uptake was determined with a 2-h euglycemic hyperinsulinemic clamp, and regional glucose uptake in femoral and arm muscles, and myocardium using 18F-fluoro-2-deoxy-D-glucose and positron emission tomography. Glucose uptake in the athletes was increased by 68% in whole body (P < 0.0001), by 99% in the femoral muscles (P < 0.01), and by 62% in arm muscles (P = 0.06), but it was decreased by 33% in the heart muscle (P < 0.05) as compared with the sedentary subjects. The total glucose uptake rate in the heart was similar in the athletes and control subjects. Left ventricular mass in the athletes was 79% greater (P < 0.001) and the meridional wall stress smaller (P < 0.001) as estimated by echocardiography. VO2max correlated directly with left ventricular mass (r = 0.87, P < 0.001) and inversely with left ventricular wall stress (r = -0.86, P < 0.001). Myocardial glucose uptake correlated directly with the rate-pressure product (r = 0.75, P < 0.02) and inversely with left ventricular mass (r = -0.60, P < 0.05) or with the whole body glucose disposal (r = -0.68, P < 0.01). Thus, in athletes, (a) insulin-stimulated glucose uptake is enhanced in the whole body and skeletal muscles, (b) whereas myocardial glucose uptake per muscle mass is reduced possibly due to decreased wall stress and energy requirements or the use of alternative fuels, or both.

Glucose-free fatty acid cycle operates in human heart and skeletal muscle in vivo.

Positron emission tomography permits noninvasive measurement of regional glucose uptake in vivo in humans. We employed this technique to determine the effect of FFA on glucose uptake in leg, arm, and heart muscles. Six normal men were studied twice under euglycemic hyperinsulinemic (serum insulin approximately 500 pmol/liter) conditions, once during elevation of serum FFA by infusions of heparin and Intralipid (serum FFA 2.0 +/- 0.4 mmol/liter), and once during infusion of saline (serum FFA 0.1 +/- 0.01 mmol/liter). Regional glucose uptake rates were measured using positron emission tomography-derived 18F-fluoro-2-deoxy-D-glucose kinetics and the three-compartment model described by Sokoloff (Sokoloff, L., M. Reivich, C. Kennedy, M. C. Des Rosiers, C. S. Patlak, K. D. Pettigrew, O. Sakurada, and M. Shinohara. 1977. J. Neurochem. 28: 897-916). Elevation of plasma FFA decreased whole body glucose uptake by 31 +/- 2% (1,960 +/- 130 vs. 2,860 +/- 250 mumol/min, P less than 0.01, FFA vs. saline study). This decrease was due to inhibition of glucose uptake in the heart by 30 +/- 8% (150 +/- 33 vs. 200 +/- 28 mumol/min, P less than 0.02), and in skeletal muscles; both when measured in femoral (1,594 +/- 261 vs. 2,272 +/- 328 mumol/min, 25 +/- 13%) and arm muscles (1,617 +/- 411 to 2,305 +/- 517 mumol/min, P less than 0.02, 31 +/- 6%). Whole body glucose uptake correlated with glucose uptake in femoral (r = 0.75, P less than 0.005), and arm muscles (r = 0.69, P less than 0.05) but not with glucose uptake in the heart (r = 0.04, NS). These data demonstrate that the glucose-FFA cycle operates in vivo in both heart and skeletal muscles in humans.

Acute doxorubicin cardiotoxicity involves cardiomyocyte apoptosis.

Despite well-documented cardiotoxic effects, doxorubicin remains a major anticancer agent. To study the role of myocardial apoptosis following doxorubicin administration, male Wistar rats were exposed to 1.25, 2.5, and 5 mg/kg of i.p. doxorubicin and terminated on days 1-7 in groups of five. Doxorubicin caused a significant (P < 0.001) and dose-dependent induction of cardiomyocyte apoptosis at 24-48 h after the injection. Repeated injections of 2.5 mg/kg given every other day resulted in peaks of apoptosis at 24 h after each injection. However, no additive effect of repeated dosing was noted. In histological samples, alterations in the cytoskeletal apparatus with focal loss of contractile elements were seen after a single injection. Myocyte necrosis was absent. Thus, acute doxorubicin-induced cardiotoxicity involves cardiomyocyte apoptosis, a potentially preventable form of myocardial tissue loss.

Myocardial glucose uptake in patients with NIDDM and stable coronary artery disease.

Whole body insulin resistance characterizes patients with NIDDM, but it is not known whether insulin also has impaired ability to stimulate myocardial glucose uptake (MGU) in these patients. This study was designed to evaluate MGU as measured by 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) and positron emission tomography (PET) in patients with NIDDM and stable coronary artery disease (CAD) under standardized metabolic conditions. Eight patients with NIDDM, 11 nondiabetic patients with CAD, and 9 healthy control subjects were enrolled in the study. MGU was quantitated in the normal myocardial regions with [18F]FDG and PET and the whole body glucose disposal by glucose-insulin clamp technique (serum insulin, -430 pmol/l). Plasma glucose and serum insulin concentrations were comparable in all groups during PET studies. The whole body glucose uptake was 45% lower in NIDDM patients (22 +/- 9 micromol x min(-1) X kg(-1) body wt [mean +/- SD]), compared with healthy control subjects (40 +/- 17 micromol x min(-1) x kg(-1) body wt, P < 0.05). In CAD patients, whole body glucose uptake was 30 +/- 9 micromol x min(-1) x kg(-1) body wt (NS between the other groups). MGU was similar in the normal segments in all three groups (69 +/- 28 micromol x min(-1) x 100 g(-1) in NIDDM patients, 72 +/- 17 micromol x min(-1) x 100 g(-1) in CAD patients, and 76 +/- 10 micromol x min(-1) x 100 g(-1) in healthy control subjects, NS). No correlation was found between whole body glucose uptake and MGU. As studied by [18F]FDG PET under stable normoglycemic hyperinsulinemic conditions, MGU is not reduced in patients with NIDDM and CAD in spite of peripheral insulin resistance. These findings suggest that there is no significant defect in MGU in patients with NIDDM.

Vascular adhesion protein-1, intercellular adhesion molecule-1 and P-selectin mediate leukocyte binding to ischemic heart in humans.

OBJECTIVES: The expression of endothelial adhesion molecules and their functional significance in leukocyte adhesion to human myocardial blood vessels in acute myocardial infarction (AMI) were studied. BACKGROUND: Leukocyte extravasation, mediated by specific adhesion molecules, exacerbates tissue injury after restoration of blood supply to an ischemic tissue. Experimental myocardial reperfusion injury can be alleviated with antibodies that block the function of adhesion molecules involved in leukocyte emigration, but the relevant molecules remain poorly characterized in human AMI. METHODS: Semiquantitative immunohistochemistry and in vitro adhesion assays were used to study the expression and granulocyte binding abilities of different endothelial adhesion molecules in human AMI. Changes in the molecular nature of vascular adhesion protein-1 (VAP-1) were evaluated using immunoblotting. RESULTS: Certain endothelial adhesion molecules (intercellular adhesion molecule [ICAM-2], CD31 and CD73) were expressed in myocardial blood vessels homogeneously in normal and ischemic hearts, whereas others (E-selectin and peripheral lymph node addressin) were completely absent from all specimens. The synthesis of ICAM-1 was locally, and that of P-selectin regionally, upregulated in the infarcted hearts when compared with nonischemic controls. Vascular adhesion protein-1 showed ventricular preponderance in expression and alterations in posttranslational modifications during ischemia-reperfusion. Importantly, P-selectin, ICAM-1 and VAP-1 mediated granulocyte binding to blood vessels in the ischemic human heart. CONCLUSIONS: Human P-selectin, ICAM-1 and VAP-1 appear to be the most promising targets when antiadhesive interventions preventing leukocyte-mediated tissue destruction after myocardial ischemia are planned.

Coronary flow reserve is impaired in young men with familial hypercholesterolemia.

OBJECTIVES: We sought to investigate whether functional abnormalities in coronary vasomotion exist in young adults by studying 15 men (age 31 +/- 8 years [mean +/- SD]) with familial hypercholesterolemia (FH) and a matched group of 20 healthy control subjects. BACKGROUND: Precursors of morphologic coronary artery disease are known to be present in adolescents and young adults with a high risk factor profile. METHODS: Myocardial blood flow was measured at the basal state and during dipyridamole-induced hyperemia using positron emission tomography and oxygen-15-labeled water. RESULTS: Serum total and low density lipoprotein cholesterol concentrations were higher in the patients than in the control subjects (mean +/- SD): 7.7 +/- 1.9 versus 5.3 +/- 1.5 mmol/liter (298 +/- 73 vs. 205 +/- 58 mg/dl) and 6.1 +/- 1.8 versus 3.5 +/- 1.4 mmol/liter (236 +/- 70 vs. 135 +/- 54 mg/dl), respectively (both p < 0.001). The baseline myocardial blood flow was similar in the patients and control subjects: 0.92 +/- 0.24 versus 0.83 +/- 0.13 ml/g per min, respectively (p = 0.21). A significant increase in flow was observed in both groups after dipyridamole infusion, but the flow at maximal vasodilation was 29% lower in the patients: 3.19 +/- 1.59 versus 4.49 +/- 1.27 ml/g per min (p = 0.011). Consequently, coronary flow reserve (the ratio of hyperemia flow to basal flow) was 35% lower in the patients than in the control subjects: 3.5 +/- 1.6 versus 5.4 +/- 1.5 (p = 0.0008). Total coronary resistance during hyperemia was higher in the patients than in the control subjects: 36 +/- 25 versus 21 +/- 10 mm Hg/min per g per ml (p = 0.045). Coronary flow reserve was inversely associated with serum total cholesterol concentration: r = -0.43 (p = 0.009). CONCLUSIONS: Coronary flow reserve is reduced in young men with FH, and, consequently, coronary resistance during hyperemia is increased. The results demonstrate very early impairment of coronary vasomotion in hypercholesterolemic patients.

Thalidomide therapy and polyneuropathy in myeloma patients.

Thalidomide is today an increasingly used therapy in advanced and refractory myeloma patients, especially in patients relapsing after high dose therapy. One important and well-known side effect of thalidomide is polyneuropathy (PNP). The purpose of this study was to investigate 1) how severe the thalidomide-induced PNP is in patients treated for myeloma 2) which neurophysiological tests and parameters are most sensitive in detecting the thalidomide-induced PNP and 3) how neuropathic symptoms correlate with neurophysiological changes. Twelve patients received thalidomide for treatment of relapsed multiple myeloma for at least 5 months. Prior to the thalidomide treatment, all patients had been treated with chemotherapy including vincristine, and seven patients had also received cisplatin. PNP symptoms, clinical findings and neurophysiological tests before and after the therapy were evaluated. Prior to thalidomide treatment, 7 patients had minimal and one patient slight PNP. After thalidomide treatment, 4 patients had minimal, 4 patients slight, and 3 patients moderate PNP. Thalidomide-induced PNP mainly affected sensory myelinated axons, but also alpha motor neuron axons were affected to some extent. Thermal thresholds were not altered, indicating that thin myelinated and unmyelinated axons are spared. The most sensitive parameter for detecting thalidomide-induced PNP was the sensory nerve compound action potential amplitude. The neuropathic symptoms deteriorated significantly during the therapy, but clinically, no patient developed a disabling PNP that would have required interrupting the therapy. The neuropathic side effects of thalidomide seem to be acceptable in myeloma patients.

Myocardial efficiency during calcium sensitization with levosimendan: a noninvasive study with positron emission tomography and echocardiography in healthy volunteers.

Dynamic positron emission tomography (PET) with [11C]acetate allows noninvasive assessment of myocardial oxygen consumption. In combination with echocardiography, PET enables determination of cardiac efficiency (defined as useful cardiac work per unit of oxygen consumption). We used this approach to compare the effects of levosimendan, a Ca(2+)-dependent calcium sensitizer, with dobutamine and sodium nitroprusside in healthy male volunteers. The effects of levosimendan on k(mono), an index of oxygen consumption, and cardiac efficiency were neutral, whereas the hemodynamic profile was consistent with balanced inotropism and vasodilatation. Dobutamine enhanced cardiac efficiency at the expense of increased oxygen requirement, but the effects of nitroprusside on k(mono) and cardiac efficiency were neutral. This study shows the feasibility of PET in phase 1 pharmacodynamic studies and suggests potential energetical advantages of calcium sensitization with levosimendan.

Myocardial efficiency during levosimendan infusion in congestive heart failure.

AIMS: Levosimendan, a novel calcium-dependent calcium sensitizer of the myocardial contractile proteins, also enhances diastolic relaxation and induces peripheral vasodilation by opening potassium channels. To assess the combined energetical effects of levosimendan infusion in vivo, we performed positron emission tomography in patients with decompensated chronic heart failure. METHODS AND RESULTS: Eight hospitalized patients with New York Heart Association functional class III or IV heart failure received levosimendan or placebo intravenously in a randomized double-blind cross-over study. During steady-state, dynamic positron emission tomography with [11C]acetate was used to assess myocardial oxygen consumption and [15O]H2O to measure myocardial blood flow. Cardiac performance and dimensions were assessed by pulmonary artery catheterization and echocardiography. Compared with healthy volunteers, myocardial oxygen consumption during placebo was elevated in the right ventricle but comparable in the left ventricle. During administration of levosimendan, cardiac output increased by 32% (P = .002) mainly because of higher stroke volume. Coronary, pulmonary, and systemic vascular resistance values were significantly reduced. Mean myocardial blood flow increased from 0.76 to 1.02 mL/min/g (P = .033). Levosimendan was neutral on myocardial oxygen consumption and left ventricular efficiency, but it improved right ventricular mechanical efficiency by 24% (P = .012). CONCLUSIONS: Levosimendan has an energetically favorable short-term profile in the treatment of congestive heart failure. It enhances cardiac output without oxygen wasting, particularly by improving efficiency in the right ventricle.

Labelling lymphocytes with technetium99m-hexamethyl propyleneamine oxime for scintigraphy: an improved labelling procedure.

Leukocyte scintigraphy has been used as a standard diagnostic procedure for the detection of inflammation in vivo. In this study, we developed a method of labelling purified lymphocytes with technetium99m-hexamethyl propyleneamine oxime (Tc99m-HMPAO) without significantly impairing their function. This was confirmed by measurements of in vitro lymphocyte adhesion and migration and of both necrotic and apoptotic cell death. The results of the in vitro control studies indicate that the dysfunction of leukocytes caused by Tc99m-HMPAO labelling can be minimized by using a gentle labelling method and low Tc99m activity. Because lymphocytes have been thought to participate specifically in the pathogenesis of inflammatory bowel disease (IBD), we compared scintigraphies obtained with Tc99m-HMPAO-labelled purified lymphocytes and mixed leukocytes in colitis patients. We found that a lower number of Tc99m-HMPAO-labelled peripheral blood lymphocytes accumulated in the inflamed colon during the first 4 h than labelled mixed leukocytes. The results are likely to reflect the dissimilar kinetics of lymphocyte traffic compared with granulocytes in IBD. We do not recommend the use of Tc99m-HMPAO-labelled purified lymphocytes as a diagnostic tool in chronic colitis. However, the in vitro data indicate that Tc99m-HMPAO-labelled lymphocytes may be suitable for studying short term lymphocyte recirculation and lymphocyte kinetics in other types of inflammation.

Artifactual inhomogeneities in myocardial PET and SPECT scans in normal subjects.

UNLABELLED: It has been well established that PET and SPECT scans of human myocardium are subject to partial volume related effects, which can cause artifactual regional variations in activity around the myocardium. This study investigated the sources and magnitude of such artifactual inhomogeneity in subjects with normal cardiac function. METHOD: Using multi-slice, gated MRI scans from 9 normal subjects, we examined separately the influences on measured activity of wall motion, axial resolution and the relationship between wall thickness and in-plane resolution. RESULTS: Two patterns of artifactual inhomogeneity were found: a depression in activity at the antero-apex and an elevation in activity in the free wall compared with the septum. Thus, in ungated PET images the true apical/septal ratio was artifactually reduced by a factor of 0.89 (0.92 for SPECT), while the true free wall/septal ratio was enhanced by a factor of 1.12 (1.19 for SPECT). Gating improved uniformity in end-systolic (ES) images but degraded uniformity in end-diastolic (ED) images. With gating, the true PET apical/septal ratio was artifactually reduced by only 0.97 at ES, and 0.82 at ED. Similar behavior was found for SPECT. Improvements in axial resolution were found to have little effect on artifactual variations. CONCLUSION: We find that the relationship between in-plane resolution and wall thickness, but not axial resolution, is of prime importance in determining the degree of artifactual inhomogeneity in ungated scans of normal human myocardium. Gating improved ES but degraded ED homogeneity.

Heart and skeletal muscle glucose disposal in type 2 diabetic patients as determined by positron emission tomography.

Myocardial and skeletal muscle glucose uptake was examined in 9 type 2 diabetic patients and 13 control subjects using PET and the insulin clamp technique. All subjects had clinically stable coronary heart disease. To simulate the clinical situation, diabetic patients were kept slightly hyperglycemic during the clamp study. Consequently, there were no differences in skeletal muscle or total body glucose disposal between the two groups. With PET, myocardial glucose uptake was 12-20-fold greater than that in skeletal muscle in both groups. However, in the diabetic patients, myocardial glucose uptake was 39% lower (p < 0.05) than in the control subjects. These data suggest a defect in myocardial glucose utilization in type 2 diabetes and emphasize the need for standardized metabolic conditions in diabetic patients during 18FDG PET imaging.

Enhancement of myocardial [fluorine-18]fluorodeoxyglucose uptake by a nicotinic acid derivative.

UNLABELLED: Recently, the euglycemic hyperinsulinemic clamp technique was shown to give excellent image quality during metabolic steady-state conditions. Acipimox is a new potent nicotinic acid derivative that rapidly reduces serum free fatty acid (FFA) levels by inhibiting lipolysis in peripheral tissue. METHODS: To compare the effects of acipimox administration and insulin clamp on [18F]fluorodeoxyglucose ([18F]FDG) uptake and myocardial glucose utilization, five nondiabetic and seven type II diabetic patients who had had previous myocardial infarctions were studied twice: once during a clamp study and once after the administration of acipimox (2 x 250 mg orally). All patients also underwent resting SPECT perfusion imaging prior to PET scans. RESULTS: The patients tolerated acipimox well. Although fasting plasma glucose levels were higher in diabetic patients (9.2 +/- 3.4 versus 5.5 +/- 0.3 mM, p = 0.03), they were decreased both during clamping and after acipimox; during imaging, no significant differences between the groups and approaches were detected. By visual analysis, the image quality and myocardial [18F]FDG uptake patterns were similar during clamping and after acipimox. Compared with the relative [18F]FDG uptake values obtained during clamping, acipimox yielded similar results in normal, mismatch and scar segments (r = 0.88, p = 0.0001). Similar rMGU values were also obtained during both approaches. CONCLUSION: Thus, PET imaging with [18F]FDG after the administration of acipimox is a simple and feasible method for clinical viability studies both in nondiabetic and diabetic patients. It results in excellent image quality and gives rMGU levels similar to the insulin clamp technique.

Automated electrocardiographic scores to estimate myocardial injury size during the course of acute myocardial infarction.

The automated ST-elevation score at admission and maximal QRS score during hospitalization provide good estimates of biochemical injury size during the course of first myocardial infarction. Being easily computerized, such scores could be used routinely to monitor the effect of injury-limiting therapy.

Comparison of autonomic withdrawal in men with obstructive sleep apnea syndrome, systemic hypertension, and neither condition.

Obstructive sleep apnea syndrome is characterized by obesity, nocturnal breathing abnormalities, arterial hypertension, and an increased number of cardiovascular events. Sympathetic activity is increased during nocturnal apneic episodes, which may mediate the cardiovascular complications of sleep apnea. We studied 15 male subjects with obstructive sleep apnea syndrome and associated hypertension, 54 subjects with mild to moderate essential hypertension, and 25 healthy normotensive men. Cardiovascular autonomic control was assessed using frequency domain measures of heart rate variability (HRV) during a controlled breathing test and during orthostatic maneuver. Compared with normotensive and hypertensive groups, total power and low- and high-frequency components of HRV during controlled breathing were significantly (analysis of variance, p<0.0001) lower in the obstructive sleep apnea syndrome. During the orthostatic maneuver, the change in total power of HRV was different between the 3 groups (analysis of variance, p = 0.004). The total power of HRV tended to increase in the normotensive (4.11+/-12.29 ms2) and in hypertensive (2.31+/-12.65 ms2) groups, but decreased (1.13+/-1.23 ms2) in the hypertensive group with obstructive sleep apnea syndrome. According to multivariate regression analysis, age and sleep apnea were the major independent determinants of HRV. This study found that an abnormal response to autonomic nervous tests characterizes hypertension in overweight subjects with obstructive sleep apnea syndrome. This could be due to autonomic withdrawal or supersaturation of the end-organ receptors by excessive and prolonged sympathetic stimulation. Our results also show the reduced response of orthostatic maneuver and controlled breathing in the hypertensive group compared with the normotensive group.

Cardiac positron emission tomography imaging with [11C]hydroxyephedrine, a specific tracer for sympathetic nerve endings, and its functional correlates in congestive heart failure.

The integrative mechanisms of autonomic dysfunction in congestive heart failure (CHF) remain poorly understood. We sought to study cardiac retention of [11C]hydroxyephedrine (HED), a specific tracer for sympathetic presynaptic innervation, and its functional correlates in CHF. Thirty patients with mild to moderate heart failure underwent resting cardiac HED positron emission tomography imaging, spectrum analysis testing of systolic pressure and heart rate variability in the resting supine and 70 degrees head-up tilt positions, and testing of baroreflex sensitivity. Compared with control subjects, global myocardial HED retention index was reduced by 30% (p <0.01) in patients with CHF. The HED retention index did not correlate significantly with heart rate variability. However, it correlated with baroreflex sensitivity at rest (r = 0.43, p = 0.05) and with systolic pressure low-frequency (0.03 to 0.15 Hz) variability at head-up tilt (r = 0.76, p <0.01), as well as with low-frequency systolic pressure variability response from baseline to tilt (r = 0.75, p <0.01). We conclude that cardiac HED retention is reduced in patients with CHF. This correlates with blunted vascular sympathetic effector responses during posture-induced reflex activation and baroreflex control of heart rate, suggesting an interdependence between cardiac presynaptic innervation abnormalities and neural mechanisms important to blood pressure maintenance in CHF.

Celiprolol augments the effect of physical exercise on insulin sensitivity and serum lipid levels in chronic heart failure.

PURPOSE: Impaired insulin sensitivity has been linked with chronic heart failure (CHF). Exercise has a beneficial effect on insulin sensitivity in healthy subjects. It is used also as an adjunctive therapy in patients with CHF. We studied the effect of randomized treatment with celiprolol, a vasodilating beta(1)-adrenoceptor antagonist, 200 mg once daily (n=20) or placebo (n=11) on serum lipid levels and insulin sensitivity in patients with CHF. In addition, all subjects participated in a 6-month exercise training protocol. Thirteen subjects in the celiprolol and eight subjects in the control group were on additional beta(1)-adrenoceptor antagonist as part of their tailored CHF therapy. Insulin sensitivity was determined using the hyperinsulinemic euglycemic clamp test (diabetic subjects excluded, n=11 for the celiprolol group and n=8 for the placebo group). RESULTS: Insulin sensitivity index (ISI) increased by 33% (P<0.05) in the celiprolol group and by 17% (NS) in the control group. The mean increase in the whole group was 20% [from 68.2+/-11.5 to 81.7+/-10.7 ml/min/kg (mU/l), P<0.05]. No change was found in the total cholesterol level. HDL cholesterol levels increased by 12% (from 0.98+/-0.05 to 1.10+/-0.05 mmol/l, P<0. 005), and HDL/total cholesterol and HDL/LDL cholesterol ratios by 15% and 16%, respectively (P<0.005). The increase in serum fasting HDL cholesterol level was greater in the celiprolol-treated group (P<0.05). At baseline ISI correlated with maximal oxygen uptake (r=0. 65, P<0.0001) and body mass index (r=-0.55, P<0.001). The change in ISI correlated weakly with the improvement in muscle exercise capacity (r=0.53, P<0.05). CONCLUSIONS: Insulin sensitivity and serum lipid levels may be favorably affected by exercise training in subjects with mild-to-moderate CHF. Celiprolol, a vasodilating beta1- selective adrenoceptor antagonist, potentiates this effect.

Bactericidal/permeability-increasing protein (BPI) in sepsis correlates with the severity of sepsis and the outcome.

OBJECTIVE: To compare the prognostic significance of bactericidal/permeability-increasing protein (BPI), group II phospholipase A2 (PLA2-II), C-reactive protein (CRP), tumour necrosis factor-alpha (TNF), interleukin-8 (IL-8) and interferon-gamma (IFN) in terms of predicting severity of sepsis and outcome. DESIGN: A prospective study. SETTING: Medical intensive care unit (ICU) of a university hospital. PATIENTS: Thirty-four patients with severe sepsis requiring ICU treatment. MEASUREMENTS AND RESULTS: The levels of BPI, PLA2-II, CRP, TNF, IL-8 and IFN were measured in these 34 patients. High levels of BPI were associated particularly with Gram-negative sepsis. BPI and BPI/neutrophil ratios correlated positively with PLA2-II, CRP, TNF and IL-8 and negatively with blood pressure. At 24 h, BPI/neutrophil ratios, IL-8 and Simplified Acute Physiology Scores II (SAPS II) scores were higher in non-survivors than in survivors. No such associations were noted in the levels of CRP, PLA2-II, TNF or IFN. The areas under the curve (AUC(ROC)s) of SAPS II scores and IL-8 were higher than AUC(ROC) of BPI/neutrophil ratio. CONCLUSION: The BPI and BPI/neutrophil ratios may serve as adjunctive tools to illustrate the severity of sepsis. However, their predictive power for sepsis-related death was not comparable to that of SAPS II scores and IL-8.

Reduced heart rate variability in hypertension: associations with lifestyle factors and plasma renin activity.

Limited information exists on the relations between heart rate variability, hypertension, lifestyle factors and renin-angiotensin-aldosterone system. A total of 191 newly diagnosed yet untreated hypertensive men and women, 35-54 years of age, were compared with an age- and gender-stratified random population sample of 105 normotensive men and women to find out independent determinants of heart rate variability. Heart rate variability was computed from 5-min ECG time series using the standard deviation of normal-to-normal RR intervals (SDNN), the square root of the mean of squared differences between adjacent normal RR intervals (RMSSD) and the fast Fourier transform spectral analysis. All absolute measures of heart rate variability were reduced in hypertension (P<0.001 for each, ANOVA). In multivariate regression analyses, reduced heart rate variability was independently associated with higher heart rate (P<0.001 for all absolute measures of heart rate variability), higher age (P=0.001 for SDNN, total and LF powers; P<0.001 for RMSSD and HF power) and higher mean arterial pressure (P<0.05 for total power, P<0.01 for the other absolute measures) but not with sodium and alcohol intakes, body mass index and smoking. Increased plasma renin activity (PRA) was an independent attributor of reduced HF power (P<0.05) and reduced RMSSD (P<0.01). Increased blood pressure and heart rate are associated with decreased heart rate variability without any direct effects on heart rate variability of lifestyle factors. High PRA is an independent determinant of diminished modulation of vagal activity.

Increased pulse pressure is associated with reduced baroreflex sensitivity.

Although pulse pressure (PP), heart rate variability (HRV) and baroreflex sensitivity (BRS) have been shown to predict cardiovascular events and mortality in various populations, their relationships have not been clarified. We examined these associations in two separate population-based samples of healthy middle-aged subjects. In population 1, data were obtained from 149 subjects (71 men and 78 women) aged 35-64 (mean 47.7) years, and in population 2, from 214 subjects (88 men and 126 women) aged 40-62 (mean 50.5) years. Increased 24-h ambulatory PP was related to decreased cross-spectral BRS independent of age and gender (beta=-0.28, P<0.001 for population 1; beta=-0.22, P=0.003 for population 2). This association remained significant when 24-h ambulatory diastolic blood pressure, body mass index, smoking and alcohol intake were added as covariates in the multivariate analysis. Increased ambulatory PP was also associated with increased beat-to-beat systolic arterial pressure variability. Associations between ambulatory PP and HRV were not significant after controlling for age and gender. Our results suggest that elevated PP does not affect overall HRV, but it interferes with baroreflex-mediated control of the heart rate. This association may be due to a common denominator, such as arterial stiffness, for PP and BRS.