Determinants of post-ischaemic reactive hyperaemia in patients with diabetes mellitus type II

Dysfunction of resistance arteries is thought to be an early reversible stage in the development of atherosclerosis. Dynamics of post-ischaemic reactive hyperaemia are believed to constitute a useful tool for monitoring resistance vessel function. Patient characteristics influencing reactive hyperaemia, however, need to be defined more precisely. Since reactive hyperaemia is a dynamic process, yielding submaximal peak values after 5 min of ischaemia, this period was chosen to investigate the determinants of reactive hyperaemia in 100 type II diabetic patients as well as in 61 control subjects. Reactive hyperaemia was measured by venous-occlusion plethysmography; clinical and laboratory data were acquired by routine methods. Statistical comparison was performed with SYSTAT 5·0 for Apple Macintosh. Overall, no significant differences between diabetic patients and controls were observed by group comparison. In control subjects, only gender showed an influence on peak reactive hyperaemia (females 40·5 ± 15·3; males 51·8 ± 17·7 ml min^–1 100 ml^–1, P<0·01). In diabetic patients, in addition to gender, actual blood glucose (r=0·377, P<0·05) and meal intake (non-fasting 42·8 ± 19·2; fasting 51·2 ± 19·5 ml min^–1 100 ml^–1, P<0·05) were found to influence reactive hyperaemia. Further investigation revealed a loss of the correlation between peak reactive hyperaemia and actual blood glucose observed in the fasting state (P<0·001) in non-fasting diabetic patients, indicating an influence of meal intake on resistance vessel reactivity. Our results suggest that, in diabetic subjects, in addition to gender actual blood glucose and the postprandial situation impacts on peak reactive hyperaemia.     

Postprandial impairment of resistance vessel function in insulin treated patients with diabetes mellitus type‐2

Reduced postischaemic reactive hyperaemia, is considered a marker of impaired resistance vessel function. Acute postprandial hyperlipidaemia has been shown to induce vascular dysfunction. In the present study, the impact of postprandial hyperglycaemia on resistance vessel reactivity was investigated in insulin treated type‐2 diabetic patients. The study was performed in 16 insulin treated type‐2 diabetics (eight male/eight female, age 47 ± 3 years, HbA1c 7·2 ± 0·2) and 16 controls. Reactive hyperaemia was measured in the forearm by venous occlusion plethysmography after 5 min of ischaemia in the fasting state and 90 min after a test meal. In diabetics, blood glucose increased from 8·7 ± 1·1 to 15·3 ± 1·0 mmol l^?1 (P<0·001) postprandially. This resulted in (i) a significant increase of resting blood flow (3·4 ± 0·3 to 4·8 ± 0·4 ml min^?1 100 ml^?1, P<0·01) and (ii) in a reduced peak reactive hyperaemia (52·3 ± 7·4 to 36·8 ± 4·3 ml min^?1 100 ml^?1, P<0·005). In controls, a similar effect of the meal on resting flow was observed but reactive hyperaemia was unaltered. In the absence of a test meal, basal flow as well as peak reactive hyperaemia remained unchanged in diabetic as well as in non‐diabetic subjects. Our data provide evidence that in the postprandial state resistance vessel reactivity becomes reduced in insulin treated type‐2 diabetic patients.     

Sustained hyperaemia stimulus is necessary to induce flow-mediated dilation of the human brachial artery

We studied the relative importance of the magnitude and duration of the shear stimulus to induce flow‐mediated dilation (FMD) in the brachial artery of 10 healthy men by ultrasound imaging. The shear stress stimulus was induced by different durations of reactive hyperaemia following 15‐min forearm occlusion. The control condition of continuous postocclusion hyperaemia was compared to 20, 40 and 60 s of reactive hyperaemia followed by reapplication of circulatory arrest for 2 min and a second cuff release. In response to the first cuff release, peak shear rate was not different between conditions; total shear during the first minute was reduced in the 40 s and further reduced in the 20 s conditions. FMD in control (10·0 ± 3·0%), 60 s (10·5 ± 3·2%) and 40 s (7·8 ± 3·6%) were greater than the 20‐s condition (2·9 ± 2·8%). At second cuff release, peak shear of the 20‐s condition was slightly reduced from the first release, but 40 and 60‐s conditions were progressively reduced. Total shear to peak dilation was reduced after the second cuff release for the 20 and 40‐s conditions and further after the 60‐s condition. FMD was maintained in the 20‐s condition (8·3 ± 3·7%) but reduced in the 40‐s (3·7 ± 1·7%) and 60‐s conditions (1·5 ± 2·6%). FMD was not related to peak shear rate after the first occlusion (r = 0·003) but was after the second cuff release (r = 0·32, P = 0·004). The FMD response was correlated with the total shear to time of peak diameter after the first (r = 0·35, P<0·001) and the second (r = 0·25, P = 0·009) cuff release.     

Effects of dipyridamole and theophylline on reactive hyperaemia in subcutaneous adipose tissue in humans

Summary. The importance of adenosine for reactive hyperaemia in subcutaneous adipose tissue was studied in healthy volunteers, using the adenosine uptake inhibitor dipyridamole (bolus 0·1 mg/kg i.v. followed by infusion of 0·7 μg/kg/min) and the adenosine receptor antagonist theophylline (4 or 6 mg/kg i.v.). Basal blood flow, total blood flow and hyperaemia (total minus basal flow) after a 20-min arterial occlusion were measured in the distal femoral region by the ¹³³Xe washout technique with and without drug treatment. Basal blood flow (mean±SEM) was 2·4 ± 0·3 ml/min/100 g, while total post-occlusive flow and total reactive hyperaemia were 97·3 ±8·4 and 61·8 ± 6·5 ml/100 g, respectively, without drug treatment. Basal blood flow was unaffected by dipyridamole but the total flow and hyperaemia were enhanced by 49 ± 24 and 60 ± 31%, respectively (P<·005 for both). This enhancement was due to increases in both amplitude and duration of the hyperaemia. Neither basal blood flow, total post-occlusive flow nor hyperaemia were significantly altered by theophylline. The amplitude of the enhanced hyperaemia during dipyridamole was not significantly counteracted by simultaneous theophylline treatment (6 mg/kg) but the duration of hyperaemia was reduced from 13 ± 1 to 8 ± 1 min (P<0·01). The results suggest that endogenous adenosine does not regulate basal blood flow or reactive hyperaemia of limited duration in human adipose tissue. However, reactive hyperaemia may be enhanced by pharmacological elevation of endogenous adenosine levels.     

Evaluation of endothelial function using finger plethysmography

Background: The aims of this study were to establish the optimum duration of blood flow occlusion to obtain maximal response and to compare the response after lower‐arm and upper‐arm occlusion. Methods: Pulse wave amplitude was analysed using a novel finger plethysmograph (EndoPat; Itamar). For measuring reactive hyperaemic index (RHI) induced by forearm cuff occlusion, 30 healthy subjects were examined at different days in a random order of four cuff occlusion times (1·5, 3, 5 and 8 min). RHI induced by 5 min upper‐arm cuff occlusion was also measured in 20 subjects. Results: Average RHI was lower with 1·5 and 3 min forearm occlusion compared with 8 min forearm occlusion (P = 0·002 and P = 0·024). There was no significant difference between values of 5 min and 8 min forearm occlusion and between 5 min forearm and 5 min upper‐arm occlusion (P = 0·1). All subjects reported less discomfort after forearm occlusion compared with upper‐arm occlusion. Conclusion: Maximum response was reached after 5 min of blood flow occlusion and therefore this occlusion time is recommended. The response after forearm and upper‐arm occlusion did not differ significantly. Forearm occlusion might be preferred as this caused less discomfort.     

Effects of a high‐fat meal on resistance vessel reactivity and on indicators of oxidative stress in healthy volunteers

High fat meals postprandially impair macrovascular endothelial function and a link to increased oxidative stress is suggested. Few information, on the other hand, exists on the effect of postprandial hyperlipidaemia on resistance vessel function. Under normal circumstances this vascular bed regulates tissue perfusion and, by controlling flow, impacts on macrovascular nitric oxide formation. The impact of a high fat meal (1200 kcal, 90 g fat, 46 g protein and 47 g carbohydrates) on postprandial resistance vessel reactivity and on indicators of oxidative stress was studied in 11 healthy subjects by venous‐occlusion plethysmography using another six subjects as time control group. Ingestion of the test meal resulted in a pronounced increase of serum triglycerides from 1·05 ± 0·61 mmol l^?1 in the fasting state to peak postprandial values of 1·94 ± 0·41 mmol l^?1 (P < 0·001) reached after 4 h and a return to baseline after 8 h. Fasting peak reactive hyperaemia (RH) was 19·6 ± 2·4 ml min^?1 (100 ml)^?1. Two hours after ingestion of the test meal peak RH was transiently reduced to 16·8 ± 2·2 ml min^?1 (100 ml)^?1 (P < 0·05). No alteration of resting forearm perfusion was observed. The time course of peak RH suggested a potential biphasic effect of the test meal with an early impairment and a late increase of RH. Ingestion of a lipid rich test meal did not exert any influence on either total plasma antioxidant capacity given in trolox equivalents (513 ± 26 μmol l^?1 at baseline) or on plasma peroxides measured as H₂O₂ equivalents (469 ± 117 μmol l^?1). Our results suggest that ingestion of a meal containing 90 g of fat results in a transient impairment of reactive hyperaemia in healthy subjects but these vascular alterations are not accompanied by signs of systemically increased oxidative stress.     

Diameter and compliance of the greater saphenous vein - effect of age and nitroglycerine

Objectives: The greater saphenous vein (GSV) is commonly used in autologous vein graft surgery. GSV diameter has proven to influence graft patency, and furthermore venous compliance might be of importance. The purpose of the study was to evaluate the effect of age on GSV diameter and compliance, and to evaluate the effect of nitroglycerine (NTG). Methods: The diameter and compliance of the GSV, with and without NTG, were examined with B‐mode ultrasound in 12 elderly (70·3 ± 1·2 year) and 15 young (25·1 ± 0·6 year) men. The GSV diameter at the thigh and calf level was measured at rest, after 6 min of venous stasis (60 mmHg) and after NTG administration. Pressure–area curves during a linear venous pressure decrease were produced. Venous compliance was calculated using the quadratic regression equation (area) = β₀ + β₁ (cuff pressure) + β₂ (cuff pressure)². Results: GVS diameter between the groups showed significant lower diameter in elderly compared to young men (P<0·05). Venous occlusion increased GSV diameter in elderly men (P<0·01) as well as young men (P<0·001). NTG increased GSV diameter in elderly men (P<0·01) with an equal trend in young men. During venous occlusion, after administration of NTG, GSV diameter increased further in both elderly (P<0·01) and young men (P<0·001). GSV compliance was decreased in elderly (β₁, 0·037 ± 0019, β_2,?0·000064 ± 00017) versus young men (β₁, 0·128 ± 0·013, β₂, ?0·00010 ± 000018) [P<0·001 (β₁), P<0·02 (β₂)]. Conclusions: Baseline GSV diameter as well as GSV compliance is decreased in elderly men compared to the young subjects. As reduced GSV diameter as well as reduced compliance is related to decreased graft patency, these findings might be of importance for the uses of GSV as graft material in cardiovascular bypass surgery. The clinical value has to be clarified in future studies.     

Endothelium-independent dilation in children and adolescents

Peak brachial artery dilation post-nitroglycerin (NTG) administration occurs between 3 and 5 min in adults. The purpose of this study was to identify the time to peak dilation response to sublingual NTG (0·3 mg) in youth. Endothelium-independent dilation (EID) was measured in 198 healthy (113 males, 85 females) youth (6-18 years) via ultrasound imaging of the brachial artery following NTG administration. Time to peak EID was 268 s following NTG administration, with no significant (P = 0·6) difference between males and females. There was a significant (P<0·001) difference between EID post-NTG at the 3 versus 4 min, 4 versus 5-min, and 3 versus 5 min time points. Peak EID (males: 24·8 ± 0·5 versus females: 25·3 ± 0·6%, P = 0·6) was not significantly different after accounting for baseline diameter. Peak response to NTG administration occurs between 4 and 5 min. The results demonstrate the importance of measuring EID up to 5-min post-NTG administration in youth.     

Cutaneous reactive hyperaemia is unaltered by dietary nitrate supplementation in healthy humans

The purpose of this study was to determine whether nitrate supplementation augments cutaneous reactive hyperaemia. Seven participants were tested pre‐ and postnitrate supplementation (25 ml beetroot juice); participants consumed one shot per day for 3 days. Participants were instrumented with two microdialysis fibres: control (Ringer's solution) and NO synthase inhibition (20 mM L‐NAME). Skin blood flow was measured via laser‐Doppler flowmetry (LDF). A blood pressure cuff was placed on the experimental arm and inflated to 250 mmHg for 5 mins to occlude arterial inflow. The cuff was released, and the resultant reactive hyperaemia was measured. Blood pressure was continuously measured via plethysmography from a finger on the non‐experimental arm. Cutaneous vascular conductance was calculated (LDF/MAP) and normalized to maximal vasodilatation (%CVC_max). Only diastolic blood pressure was reduced following nitrate supplementation (71 ± 2 vs. 66 ± 1 mmHg; P<0·05). There was no effect of nitrate supplementation on peak reactive hyperaemia at control (Pre: 52 ± 3 vs. Post: 57 ± 2%CVC_max) or L‐NAME (Pre: 52 ± 2 vs. Post: 59 ± 4%CVC_max) sites. There was no effect of nitrate supplementation on total reactive hyperaemia at either control (Pre: 4197 ± 943 vs. Post: 4523 ± 1040%CVC_max * sec) or L‐NAME (Pre: 5108 ± 997 vs. Post: 5694 ± 1002%CVC_max * sec) sites. These data suggest cutaneous reactive hyperaemia is unaffected by dietary nitrate supplementation in healthy humans.     

Elevated augmentation index derived from peripheral arterial tonometry is associated with abnormal ventricular–vascular coupling

Background: Although typically derived from the contour of arterial pressure waveform, augmentation index (AIx) may also be derived from the digital pulse volume waveform using finger plethysmography (peripheral arterial tonometry, PAT). Little is known regarding the physiologic correlates of AIx derived from PAT. In this study, we investigated the relation of PAT‐AIx with measures of ventricular–vascular coupling. Methods: Pulse volume waves were measured via PAT and used to derive AIx. Using 2‐dimensional echocardiography, effective arterial elastance index (EaI) was estimated as end‐systolic pressure/stroke volume index. Left ventricular (LV) end‐systolic elastance index (E_LVI) was calculated as end‐systolic pressure/end‐systolic volume index. Ventricular–vascular coupling ratio was defined as EaI/E_LVI. Results: Given the bi‐directional nature of ventricular–vascular uncoupling as measured by echocardiography, patients were separated into three groups: low EaI/E_LVI (<0·6, n = 21), optimal EaI/E_LVI (mean 0·6–1·2, n = 16) and high EaI/E_LVI (>1·2, n = 10). Adjusting for potential confounders (age, mean arterial pressure, height and heart rate), patients with optimal EaI/E_LVI had lower AIx (1 ± 4%, P<0·05) compared to those with low EaI/E_LVI (13 ± 4%) and high EaI/E_LVI (19 ± 5%). Conclusions: Abnormal ventricular–vascular coupling, arising from either increased effective arterial elastance or increased ventricular elastance, is associated with increased AIx as measured by PAT. Additional research is needed to examine other vascular correlates of PAT‐AIx.     

Intensity of Nordic Walking in young females with different peak O2 consumption

The purpose of this cross‐sectional study was to determine the physiological reaction to the different intensity Nordic Walking exercise in young females with different aerobic capacity values. Twenty‐eight 19–24‐year‐old female university students participated in the study. Their peak O₂ consumption (VO₂ peak kg^?1) and individual ventilatory threshold (IVT) were measured using a continuous incremental protocol until volitional exhaustion on treadmill. The subjects were analysed as a whole group (n = 28) and were also divided into three groups based on the measured VO₂ peak kg^?1 (Difference between groups is 1 SD) as follows: 1. >46 ml min^?1 kg^?1 (n = 8), 2. 41–46 ml min^?1 kg^?1 (n = 12) and 3. <41 ml min^?1 kg^?1 (n = 8). The second test consisted of four times 1 km Nordic Walking with increasing speed on the 200 m indoor track, performed as a continuous study (Step 1 – slow walking, Step 2 – usual speed walking, Step 3 – faster speed walking and Step 4 – maximal speed walking). During the walking test expired gas was sampled breath‐by‐breath and heart rate (HR) was recorded continuously. Ratings of perceived exertion (RPE) were asked using the Borg RPE scale separately for every 1 km of the walking test. No significant differences emerged between groups in HR of IVT (172·4 ± 10·3–176·4 ± 4·9 beats min^?1) or maximal HR (190·1 ± 7·3–191·6 ± 7·8 beats min^?1) during the treadmill test. During maximal speed walking the speed (7·4 ± 0·4–7·5 ± 0·6 km h^?1) and O₂ consumption (30·4 ± 3·9–34·0 ± 4·5 ml min^?1 kg^?1) were relatively similar between groups (P > 0·05). However, during maximal speed walking, the O₂ consumption in the second and third groups was similar with the IVT (94·9 ± 17·5% and 99·4 ± 15·5%, respectively) but in the first group it was only 75·5 ± 8·0% from IVT. Mean HR during the maximal speed walking was in the first group 151·6 ± 12·5 beats min^?1, in the second (169·7 ± 10·3 beats min^?1) and the third (173·1 ± 15·8 beats min^?1) groups it was comparable with the calculated IVT level. The Borg RPE was very low in every group (11·9 ± 2·0–14·4 ± 2·3) and the relationship with VO₂and HR was not significant during maximal speed Nordic Walking. In summary, the present study indicated that walking is an acceptable exercise for young females independent of their initial VO₂ peak level. However, females with low initial VO₂ peak can be recommended to exercise with the subjective ‘faster speed walking’. In contrast, females with high initial VO₂ peak should exercise with maximal speed.     

Endothelial function and hemodynamics in systemic sclerosis

Introduction: Systemic sclerosis (SSc) is characterized by the development of fibrosis of skin and internal organs that is associated with vascular damage. However, its related parameters have not been fully explored. The aim of this study was to investigate endothelial function in SSc and its relationship with systolic pulmonary artery pressure and systemic arterial compliance (SAC). Methods: We studied 14 SSc females (4 with diffuse and 10 with limited cutaneous form of the disease) and 14 healthy controls matched for age and for cardiovascular risk factors. Endothelium‐dependent dilation (i.e. flow‐mediated) and endothelium‐independent (i.e. nitroglycerin‐induced) dilation of the brachial artery were measured as the percentage of change from baseline (FMD and NMD, respectively). In patients with SSc, SAC, cardiac output (CO), systemic arterial resistance and pulmonary artery pressure were estimated using echocardiography Doppler. Results: Heart rate, brachial artery pressure and body mass index did not differ between patients with SSc and controls. Flow‐mediated vasodilation (FMD) and NMD were significantly decreased in patients with SSc (10·3 ± 8·6 versus 26·6 ± 7·4%, P<0·001; 24·2 ± 8·4 versus 33·3 ± 10·1%, P<0·001, respectively). Postischaemia reactive hyperaemia was lower in patients with SSc (275 ± 185 versus 618 ± 366%, P<0·001). FMD and nitrate‐mediated dilation (NMD) were associated with CO, but not with SAC; moreover, FMD correlated with pulmonary artery pressure and peripheral arterial resistance conversely to NMD. Conclusions: Endothelium function in SSc is impaired independently to SAC. Furthermore, the severity of both small artery and pulmonary artery involvement may impact on endothelium‐dependant function.     

Simultaneous quantification of myocardial perfusion,oxidative metabolism,cardiac efficiency and pump function at rest and during supine bicycle exercise using 1‐11C‐acetate PET – a pilot study

Background: PET using 1‐¹¹C‐acetate (ACE‐PET) applied at rest is used for measuring absolute myocardial blood flow (MBF) and oxidative metabolic rate (k_mono). We evaluated the feasibility of quantitative ACE‐PET during exercise. Methods: Five endurance athletes underwent dynamic PET scanning at rest and during supine bicycle stress. Exercise was maintained at a workload of 120 Watt for 17 min. The rate‐pressure product (RPP) was recorded repeatedly. MBF, k_mono in left (LV) and right (RV) ventricular wall, cardiac output (CO), cardiac efficiency and a lung uptake value reflecting left heart diastolic pressures were calculated from the PET data using previously validated models. Results: MBF increased from 0·71 ± 0·17 to 2·48 ± 0·25 ml min^?1 per ml, LV‐k_mono from 0·050 ± 0·005 to 0·146 ± 0·021 min^?1, RV‐k_mono from 0·023 + 0·006 to 0·087 + 0·014 min^‐1, RPP from 4·7 ± 0·8 to 13·2 ± 1·4 mmHg × min^?1 × 10³ and Cardiac Output from 5·2 ± 1·1 to 12·3 ± 1·2 l min ^?1 (all P < 0·001). Cardiac efficiency was unchanged (P = 0·99). Lung uptake decreased from 1·1 ± 0·2 to 0·6 ± 0·1 ml g^?1 (P < 0·001). Discussion: A number of important parameters related to cardiac function can be quantified non‐invasively and simultaneously with a short scanning protocol during steady state supine bicycling. This might open up new opportunities for studies of the integrated cardiac physiology in health and early asymptomatic disease.     

Effect of local warming on forearm reactive hyperaemia

Summary. Measurement of minimal vascular resistance has proved useful in quantifying structural changes in regional circulations. Accurate measurement of minimal vascular resistance requires full relaxation of all resistance vessels within the region under examination. The usual procedure in humans involves the measurement of maximal forearm blood-flow following 6–10 min of forearm ischaemia. We conducted this study to find whether forearm skin was fully vasodilated by this procedure. Peak forearm blood-flow was measured by plethysmography in six healthy subjects following 10 min of ischaemia while the arm was at a neutral temperature (33°C) and while the arm was locally warmed to 42°C. Peak reactive hyperaemia blood-flow was significantly elevated by local heating (P<0·001) to 79·6 ml100ml^-1min^-1 from a value of 50·2 ml100ml^-1min^-1 during normothermia. Peak reactive hyperaemia blood-flow in the contralateral unheated forearm showed no significant change between the two periods of ischaemia (P>0·05). These findings were confirmed in four subjects by laser Doppler velocimetry, which gives a linear index of skin blood-flow. In normothermic conditions, this index rose to 0·89 V following 10 min of ischaemia and to 1·26 V with local warming to 42°C (P<0·001). Ischaemia plus local warming did not cause a further significant rise in this index of skin blood-flow (1·35 V, P>0·05). These data suggest that 10 min of ischaemia during normothermia is insufficient to relax fully cutaneous resistance vessels and that maximal forearm blood-flow is underestimated by this procedure.     

Evaluation of the transcutaneous oxygen method used at 37°C for measurement of reactive hyperaemia in the skin

Summary. The transcutaneous oxygen electrode used at an electrode temperature of 35–37°C measures changes in Po₂ at the skin surface that are mainly determined by changes in skin blood flow. Simultaneously, information about tissue Po₂ in a defined skin area can be obtained by calculation. The reproducibility of this new application of the transcutaneous PO₂ technique and factors influencing the recordings were analysed. Reactive hyperaemia was best recorded at 37°C, where the coefficient of variation (CV) was 14% and the correlation coefficient was 0·90 between duplicate measurements within 15 min (n= 57). The day-to-day variation was greater (CV 19–28%). No significant spatial differences in reactive hyperaemia were noted when the distance between the electrodes was no more than 3 cm on the same forearm. A slightly lower reactive hyperaemia was noted when the arm with the electrode was elevated above the level of the heart, as compared with a lower position. Age and sex had significant influence, children (n= 34) exhibiting a greater postocclusive peak tcPo₂ response than adults (n= 67). In adults, females (n= 30) showed significantly higher peak tcPo₂ values during reactive hyperaemia than males. This method is a new application of the tcPo₂ technique and can be used as a non-invasive tool for simultaneous blood flow and tissue Po₂ studies in microcirculatory research.     

Circulatory response to single circuit weight and walking training sessions of similar energy cost in middle‐aged overweight females

The aim of this study was to compare circulatory responses to circuit weight (CWT) and aerobic walking training sessions of similar energy cost in middle‐aged overweight females. Thirty‐three middle‐aged pre‐menopausal females participated in the experiment. They were divided into overweight (n=18, 36·2 ± 6·3 years, 166·3 ± 8·0 cm, 83·5 ± 9·7 kg, BMI 30·2 ± 3·1 kg m^–2) and non‐overweight control (n=15, 34·1 ± 6·3 years, 165·0 ± 5·6 cm, 61·6 ± 5·0 kg, BMI 22·7 ± 1·5 kg m^–2) groups. Individual physical working capacity (PWC) was measured using the cycle ergometer test (calculated at the level of predicted HR_max (205 – ½ age). A CWT session consisted of leg extension, bench press, sit‐ups and leg press exercises. The subjects performed four circuits at the maximal possible speed, using a work‐to‐rest ratio of 60 s. Blood pressure (BP) was measured during every rest period between the exercises, and the heart rate (HR) was recorded continuously during the whole CWT programme. During the walking training session, the subjects walked as fast as possible on the indoor track. The total energy cost of the walking training session was the same as during the CWT session, approximately 270 kcal, and was controlled by a CALTRAC accelerometer. HR and BP were measured every 5 min during the walking training session. The PWC index was significantly (P<0·05) higher in the overweight group in comparison with the control females (215·4 ± 76·1 and 187·9 ± 42·4 W, respectively). The resting BP was normal in both groups (<140/90 mmHg). HR was between 120 and 140 beats min^–1 during CWT and walking sessions. There were no differences in BP during both training sessions in overweight and control subjects. It was concluded that both CWT and walking training sessions were acceptable forms of physical activity to increase cardiovascular fitness in middle‐aged overweight and normal body weight females.     

Effect of polymerized-type I collagen in knee osteoarthritis. II. In vivo study

Background Polymerized‐Type I Collagen (Polymerized‐Collagen) is an anti‐inflammatory and a tissue regenerator biodrug. The aim of the study was to evaluate the efficacy and safety of intra‐articular injections of Polymerized‐Collagen in patients with knee osteoarthritis (OA). Methods and design Patients (n = 53) were treated with 12 intra‐articular injections of 2 mL of Polymerized‐Collagen (n = 27) or 2 mL of placebo (n = 26) during 6 months. Follow up period was 6 months. The primary endpoints included Western Ontario and McMaster University Osteoarthritis Index, Lequesne index, and pain intensity on a visual analogue scale (VAS). Secondary outcomes were patient global score, investigator global score and drug evaluation. Clinical improvement was determined if the decrease in pain exceeds 20 mm on a VAS and patients achieved at least 20% of improvement from baseline. Urinary levels of C‐terminal crosslinking telopeptide of collagen type II (CTXII) and serum high‐sensitivity C‐reactive protein (hsCRP) were determined by enzyme immunoassays. Statistical analysis was performed by intention to treat. Results Polymerized‐Collagen was safe and well tolerated. Patients had a statistically significant improvement (P < 0·05) from baseline vs. Polymerized‐Collagen and vs. placebo at 6 months in: Lequesne Index (13·1 ± 0·5 vs. 7·1 ± 0·7 vs. 9·6 ± 0·8; P = 0·027), WOMAC (9·0 ± 0·5 vs. 4·0 ± 0·6 vs. 5·80 ± 0·8; P = 0·032), patient VAS (60·0 ± 2·6 vs. 20·6 ± 2·4 vs. 36·1 ± 4·5; P = 0·003), physician VAS (49·8 ± 1·9 vs. 16·8 ± 2·9 vs. 29·8 ± 2·9; P = 0·002), patient global score (1·08 ± 0·1 vs. 2·7 ± 0·1 vs. 1·9 ± 0·2; P = 0·028) and analgesic usage (30·1 ± 9·4 vs. 11·0 ± 3·4 vs. 17·9 ± 4·9; P = 0·001). This improvement was persistent during the follow up. A threefold increase in CTXII was determined in placebo group. No differences were found on hs CRP and incidence of adverse events between groups. Conclusion Polymerized‐Collagen is safe and effective in the treatment of knee OA.     

Pharmacokinetics of midazolam tablet in different Chinese ethnic groups

What is known and Objectives: Subjects of different ethnic groups may respond differently to drugs. The present study was conducted to compare the oral pharmacokinetics of midazolam among healthy volunteers from five different ethnic groups in China: Han, Mongolian, Uygur, Hui and Korean. Methods: Healthy volunteers (10 Hans, 10 Mongolians, 10 Uygurs, 10 Huis and 9 Koreans) of Chinese nationality received a single oral tablet dose of 15 mg midazolam in an open label, parallel‐group study. Blood samples were collected at intervals and analysed for midazolam by high performance liquid chromatography (HPLC). Ethnic differences in pharmacokinetic parameters of midazolam using non‐compartmental methods and anova and Kruskal–Wallis rank test. Results and Discussion: Midazolam maximum concentration (C_max) was significantly lower in Mongolians than that in Hans, Uygurs, Huis and Koreans (74·9 ± 33·7, 103·1 ± 26·4, 124·8 ± 50·0, 130·0 ± 38·3 and 189·0 ± 82·1 μg/L, respectively). C_max for the Koreans were significantly greater, compared with Hans and Mongolians. The time to attain C_max (t_max) for Hans was significantly longer as compared with Koreans and Uygurs (1·5 ± 0·7, 0·8 ± 0·5, 0·6 ± 0·7 h, respectively). Midazolam terminal half‐life (t_1/2z) were 3·0 ± 0·8, 2·2 ± 0·7, 1·9 ± 0·7, 3·5 ± 1·9, 3·8 ± 2·3 h for Hans, Mongolians, Uygurs, Huis and Koreans, respectively. The differences in half‐life were significant between Koreans and Mongolians, Koreans and Uygurs, Uygurs and Huis, respectively. There were no differences between young males and females for all pharmacokinetic parameters. Double peaks in the concentration–time profiles were observed in some subjects. What is new and Conclusion: There were some significant differences in midazolam pharmacokinetics between the five Chinese ethnic groups. However, the wide intra‐ethnic variability observed in PK parameters makes predictions of midazolam kinetics, using ethnicity as predictor, unreliable.     

Myocardial velocities measured during adenosine, dobutamine and supine bicycle exercise: a tissue Doppler study in healthy volunteers

Background: Dobutamine stress echocardiography (DSE) quantified by tissue Doppler (TVI) have improved the diagnostic capacity of the procedure. Quantification of other stress modalities, e.g. adenosine stress echo (ASE) and exercise stress echocardiography (ESE) are necessary for assessing any pathophysiological differences in different forms of stress. Methods: Ten healthy individuals underwent ASE, DSE, and ESE during a span of 2–5 days. Left ventricular (LV) apical images at rest and peak stress (max) were postprocessed using TVI on a GE System FiVe equipment. ECG‐derived QRS duration (QRSD, ms), heart rate (HR, bpm), TVI‐estimated basal systolic velocities (S2V, cm s^?1), ejection time (S2T, ms) and strain (S, %) were computed off‐line and compared. Longitudinal displacement imaging, tissue tracking, was also made. Results: Data for ASE, DSE and ESE during peak stress were (HR: 84 ± 12***, 142 ± 19, 137 ± 27; P<0·001) (QRSD: 92 ± 18**, 74 ± 13, 79 ± 9; P<0·05), (S2T: 307 ± 34***, 175 ± 53, 192 ± 25; P<0·001) and (S%: 26·0 ± 3·0, 21·2 ± 7·3, 22·1 ± 5·1; P = n.s.) respectively. Velocity response, registered in the LV septum at max, was lowest during ASE (7·4 ± 1·4) highest during DSE (13·0 ± 2·7; P<0·001 versus ASE) and somewhat intermediate during ESE (11·3 ± 3·5; P<0·001 versus ASE). In contrast, strain and displacement did not differ. Conclusion: ASE evokes significantly less LV systolic response compared with both DSE and ESE. Increased velocity (P<0·05 versus rest) and strain (P>0·05) response at a much lower HR indicates that adenosine has minor effects on contraction presumably secondary to vasodilatation. Powerful chronotropic response to DSE and ESE is probably prerequisite for strong velocity response at the expense of strain and displacement. TVI‐assisted stress echocardiography thereby shows different LV systolic response in healthy individuals, depending on stress modality.     

Assessment of hypnotic effects and patient satisfaction in empirical use of sleep medicines

Objective: We assessed the hypnotic effects of and patient satisfaction with three types of hypnotics prescribed empirically: ultra‐short‐acting (US‐a), short‐acting (S‐a), and intermediate‐ and long‐acting (IL‐a) agents. Methods: We studied 310 insomniac patients (age 60·5 ± 15·0 years) treated with US‐a (n = 124), S‐a (n = 149) or IL‐a (n = 37) agents. Patients were interviewed to evaluate individual satisfaction and drug efficacy. Efficacy, as assessed by total sleep time (TST) and sleep latency time (SLT), was compared between satisfied and dissatisfied patient groups. Nocturnal awaking curve for each hypnotic was used for comparing the effects between satisfied and dissatisfied patient groups in each type of hypnotics. Results: Thirty‐two patients (25·8%) were dissatisfied with US‐a, 35 (23·5%) with S‐a and 11 (29·7%) with IL‐a. TST differed significantly between satisfied and dissatisfied groups: 424 ± 88 vs. 345 ± 101 min for US‐a (P < 0·001), 440 ± 84 vs. 359 ± 111 min for S‐a (P < 0·001) and 453 ± 96 vs. 345 ± 125 min for IL‐a (P < 0·01), respectively. With IL‐a agents, the SLT of dissatisfied patients was longer than in satisfied ones (81 ± 52 vs. 33 ± 22 min, P < 0·05). Twenty (62·5%) dissatisfied patients taking US‐a agents awoke before 05:00 hours – a rate significantly higher than satisfied patients (n = 23, 25·0%, P < 0·001). These characteristics of dissatisfied patients were reflected by the patterns of nocturnal awaking curves, although the patterns for satisfied patients were similar among the three types of hypnotics. Conclusion: Between 24% and 30% of patients were dissatisfied with their hypnotics. Shorter TST was common in dissatisfied patients receiving any agent, for reasons differing among hypnotics (longer SLT with IL‐a agents and early awakening with US‐a). Drug efficacy and patient satisfaction in empirical use of hypnotics can be assessed by nocturnal awaking curves for each hypnotic.