Evaluation of gender differences in endothelium-independent dilation using peripheral arterial tonometry

Background: A change in peripheral arterial tonometry (PAT) in response to reactive hyperaemia is often used to provide a non‐invasive measure of endothelium‐dependent dilation (EDD). Reactive hyperaemia does not allow one to quantify endothelium‐independent dilation (EID), which is part of overall vascular function. Although most research examining vascular function and cardiovascular disease has focused on EDD, there is evidence that cardiovascular risk factors may impair EID. Purpose: To examine the microvascular vasodilation response to nitroglycerin (NTG) in healthy adults using PAT. Methods: Microvascular responses to reactive hyperaemia and NTG were evaluated in 86 (41 female and 45 male) healthy subjects (age 37 ± 5 years). Beat‐to‐beat plethysmographic measurements of finger arterial pulse waves were recorded for 5 min following reactive hyperaemia. After a 10‐min rest period, sublingual NTG (0·4 mg) was administered and PAT signal changes were measured for 10 min. Peak reactive hyperaemic index (RHI) and peak NTG‐mediated index (NMI) were determined in all subjects. Results: There were no significant gender differences in peak RHI (females: 2·07 ± 0·56 versus males: 1·91 ± 0·58, P = 0·20). Mean peak NMI for all subjects was 2·78 (±1·49). Peak NMI was significantly greater in females than in males (3·11 ± 1·59 versus 2·50 ± 1·34, P = 0·05). Time to peak NMI was not significantly different between genders (7 min, 28 s [±1 min, 47 s], versus 7 min, 14 s [±1 min, 49 s], P = 0·58). Conclusion: In this population of healthy adults, peak NMI was significantly greater in females than in males. These findings suggest that gender differences exist in the microvascular vasodilation responses to NTG using PAT.     

Comparison of ultrasound assessment of flow‐mediated dilatation in the radial and brachial artery with upper and forearm cuff positions

In the published literature relating to flow‐mediated dilatation (FMD), there are substantial differences between centres in terms of normal FMD amongst healthy subjects. This present study attempts to identify the effect of differing methodologies on FMD. High frequency ultrasound was used to measure blood flow and percentage brachial and radial artery dilatation after reactive hyperaemia induced by forearm or upper arm cuff occlusion in 24 healthy subjects, less than 40 years, without known cardiovascular risk factors. FMD of the brachial artery was significantly higher after upper arm occlusion, compared with forearm occlusion, 6·4 (3·3) and 3·9 (2·6)% (P<0·05), respectively. FMD of the radial artery was significantly higher after forearm occlusion, compared with upper arm occlusion, 10·0 (4·6) and 7·9 (3·5)% (P<0·05), respectively. The percentage blood flow increase in the brachial and radial arteries after forearm and upper arm occlusion were similar. After forearm and upper arm occlusion, the radial artery percentage dilatation was greater than the brachial artery. In conclusion dilatation of the brachial artery, after reactive hyperaemia induced by upper arm occlusion, was significantly more pronounced compared with dilatation of the brachial artery after forearm occlusion, despite a similar percentage blood flow increase. The local ischaemia of the brachial artery with a proximal occlusion may explain why the brachial artery dilated more after upper arm occlusion compared with after forearm occlusion. The study has also shown that FMD of the radial artery could be assessed by B‐mode ultrasound technique. FMD was greater using the radial artery compared with the brachial artery, suggesting that the radial artery may be a useful way to assess FMD in future clinical studies.     

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.     

Evaluation of endothelium‐dependent vasodilation in the human peripheral circulation

Flow‐mediated vasodilation (FMD) in the brachial artery measured by ultrasound, and the increase in forearm blood flow (FBF) induced by local infusion of a muscarinic‐receptor agonist have both frequently been used to evaluate endothelium‐dependent vasodilation (EDV) in the human forearm. The present study intended to evaluate the relationship between these techniques and to investigate if vasodilation induced by the muscarinic receptor‐agonist methacholine (MCh) was owing to production of nitric oxide (NO). FMD during hyperaemia was assessed by ultrasound and FBF was measured by venous occlusion plethysmography during local infusion of MCh or L ‐arginine in the human forearm. Both these methods were applied in 26 individuals. In another 12 individuals forearm arterial and venous plasma concentrations of nitrate/nitrite (NOx) were measured together with FBF before and during local MCh infusion.While the change in brachial artery diameter induced by sublingually given nitroglycerine and the vasodilatory response to sodium nitroprusside (SNP) given locally in the forearm were significantly correlated (r=0·70, P<0·01), FMD showed no relationship with the vasodilation evoked by MCh (r=–0·03) or L ‐arginine (r=0·04). The five‐fold increase in FBF during MCh infusion was associated with a significant increase in venous plasma NOx concentrations (P<0·05) and a more than 11‐fold increase in forearm NOx‐release (P<0·01). Thus, a significant relationship between the two methods regarding the evaluation of endothelium‐independent vasodilation evoked by NO‐donors was found, but no relationship was found between the two methods regarding the evaluation of endothelium‐dependent vasodilation. Furthermore, vasodilation induced by MCh in the forearm seems to be induced by NO‐release.     

Adding ischaemic hand exercise during occlusion of the brachial artery increases the flow-mediated vasodilation in ultrasound studies of endothelial function

A non-invasive method has been introduced to study endothelial function by evaluating flow-mediated, endothelium-dependent vasodilation of the brachial artery. One weakness of this method is that the post-occlusion vasodilation response is very small in subjects above the age of 60 years, which is a problem when quantifying endothelial dysfunction above this age. We have therefore evaluated whether a higher post-occlusion flow stimulus and a larger vasodilation response can be achieved by adding ischaemic hand exercise during the occlusion of the brachial artery. The subject population was men (n=12), aged 60 years, free from cardiovascular disease. B-mode ultrasound images for the measurement of lumen diameter of the brachial artery were recorded before and after reactive hyperaemia induced by occlusion of the artery. Blood flow velocity was recorded intermittently using a Doppler technique. Hyperaemia was induced in two different ways: first by occlusion only and then by adding ischaemic hand exercise during the occlusion. The results showed that flow velocity was higher and the duration of flow increase was longer after ischaemic hand exercise compared with occlusion only. Two minutes after cuff pressure release, the increase in blood flow velocity was significantly higher after ischaemic hand work compared with occlusion only (P<0·01). The corresponding maximal lumen diameters after cuff pressure release were 4·63 ± 0·35 and 4·45 ± 0·34 respectively (P<0·01). The flow-mediated vasodilation increased significantly from 2·24 ± 2·00% after occlusion only to 7·42 ± 3·32% after occlusion plus ischaemic hand exercise (P<0·01). In conclusion, this study showed that a maximal endothelial-dependent vasodilation was not achieved after occlusion only in these 60-year-old men. Adding ischaemic hand exercise may therefore be of value when quantifying endothelial dysfunction in this age group.     

Effects of hypocaloric very‐low‐carbohydrate diet vs. Mediterranean diet on endothelial function in obese women*

Background Obesity is a cardiovascular risk factor associated with endothelial dysfunction, but the effect of different weight loss strategies on endothelial function is not known. The effect of diet on endothelial function in two hypocaloric diets, a very‐low‐carbohydrate diet (A) and a Mediterranean diet (M), was measured by brachial artery flow‐mediated dilation (FMD). Design Using a longitudinal, randomized, open study design, subjects were engaged in a 2‐month weight loss diet. FMD, inflammatory cytokines [interleukin‐6 (IL‐6) and tumour necrosis factor‐α] and a marker of oxidative stress [8‐iso‐prostaglandin F2α (8‐iso‐PGF2α)] were measured in subjects on three occasions: before initiating the diet (T0), after 5–7 days of dieting (T5) and after 2 months of dieting (T60). The very short‐ and medium‐term time points were established to discriminate respectively the effect of the diet itself (T5) from that of weight loss (T60). Twenty overweight/obese but otherwise healthy women (BMI: 27–34·9 kg m^?2; age 30–50 years) completed the study. Results Group A lost more weight (mean ± SEM; ?7·6 ± 0·8 kg) than group M (?4·9 ± 0·6 kg, P = 0·014) at T60. The FMD was not significantly different between the two groups at T0 (group A: 12·2 ± 2·9% vs. group B: 10·3 ± 2·3%, P = ns). In group A, FMD was significantly reduced at T5 and returned to baseline at T60; in group M, FMD increased at T5 and returned to baseline at T60 (P = 0·007 for diet × time interaction). Serum concentrations of IL‐6 and 8‐iso‐PGF2α were not significantly different between the two groups at T0 and increased significantly at T5 only in group A (P < 0·001 and P < 0·005 respectively). Conclusion As endothelial dysfunction is known to be associated with acute cardiovascular events, this study suggests that the cardiovascular risk might be increased in the first days of a very‐low‐carbohydrate diet.     

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.     

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.     

Successive deep dives impair endothelial function and enhance oxidative stress in man

The aim of this study was to assess the effects of successive deep dives on endothelial function of large conduit arteries and plasma pro‐oxidant and antioxidant activity. Seven experienced divers performed six dives in six consecutive days using a compressed mixture of oxygen, helium and nitrogen (trimix) with diving depths ranging from 55 to 80 m. Before and after first, third and sixth dive, venous gas emboli formation and brachial artery function (flow‐mediated dilation, FMD) was assessed by ultrasound. In addition, plasma antioxidant capacity (AOC) was measured by ferric reducing antioxidant power, and the level of oxidative stress was assessed by thiobarbituric acid‐reactive substances (TBARS) method. Although the FMD was reduced to a similar extent after each dive, the comparison of predive FMD showed a reduction from 8·6% recorded before the first dive to 6·3% before the third (P = 0·03) and 5·7% before the sixth dive (P = 0·003). A gradual shift in baseline was also detected with TBARS assay, with malondialdehyde values increasing from 0·10 ± 0·02 μmol l^?1 before the first dive to 0·16 ± 0·03 before the sixth (P = 0·005). Predive plasma AOC values also showed a decreasing trend from 0·67 ± 0·20 mmol l^?1 trolox equivalents (first day) to 0·56 ± 0·12 (sixth day), although statistical significance was not reached (P = 0·08). This is the first documentation of acute endothelial dysfunction in the large conduit arteries occurring after successive deep trimix dives. Both endothelial function and plasma pro‐oxidant and antioxidant activity did not return to baseline during the course of repetitive dives, indicating possible cumulative and longer lasting detrimental effects.     

The effect of enhanced external counterpulsation on C-reactive protein and flow-mediated dilation in porcine model of hypercholesterolaemia

Background: Lipid disorder causes vascular endothelial cell damage and contributes to the early development of dyslipidaemia‐induced atherosclerosis. In vivo and in vitro, it has been found that increasing shear stress can improve endothelial function. Clinically, enhanced external counterpulsation (EECP) plays important roles in the treatment of coronary artery disease by promoting arterial shear stress. The present study aims to evaluate the effect of EECP on vascular endothelial function in porcine hypercholesterolaemic model. Methods: Twenty‐six hypercholesterolaemic pigs were equally divided into EECP group (HC‐EECP group) and control group (HC group). Shear stress of a right forearm superficial artery was measured during EECP in comparison with the basal physiological status in the HC‐EECP group. Endothelial‐dependent flow‐mediated vasodilation (FMD) was applied to assess endothelial function. Serum high‐sensitivity C‐reactive protein (hs‐CRP) levels were measured at indicated time points. Results: Endothelial shear stress was increased significantly during EECP treatment (P<0·001). Compared to HC group, hs‐CRP decreased significantly by EECP at 18‐ and 36‐h, respectively (P<0·05). FMD was improved significantly by EECP compared to that of HC group at 18 h (11·09 ± 5·63%) and at 36 h (11·42 ± 2·75%) post‐EECP, P<0·05. Meanwhile, in animals of HC group, FMD was decreased from baseline 7·76 ± 3·70% to 6·75 ± 3·57% at 18 h and 5·07 ± 1·97% at 36 h, P<0·05. Conclusion: Long‐term EECP can improve endothelial function partially by an increased endothelial shear stress in hypercholesterolaemic porcine model. This implies that long‐term EECP can be used as a complementary therapeutic strategy to prevent atherosclerosis in hypercholesterolaemic patients.     

Relationship between arterial baroreflex sensitivity and exercise capacity in patients with acute myocardial infarction

To investigate the relationship between arterial baroreflex sensitivity (BRS) and exercise capacity, we examined arterial BRS and its relation to exercise capacity during upright bicycle exercise in 40 uncomplicated patients with acute myocardial infarction. Arterial BRS was measured 3 weeks (20 ± 5 days) after acute myocardial infarction and assessed by calculating the regression line relating phenylephrine‐induced increases in systolic blood pressure to the attendant changes in the R–R interval. All patients underwent graded symptom‐limited bicycle exercise with direct measurements of hemodynamic and metabolic measurements. In all patients, the average arterial BRS was 5·6 ± 2·6 ms mmHg^?1. There were no significant correlations between arterial BRS and hemodynamic measurements at rest. However, arterial BRS was negatively related to systemic vascular resistance at peak exercise (r = ?0·60, P = 0·0001) and percent change increase in systemic vascular resistance from rest to peak exercise (r = ?0·45, P = 0·003), whereas arterial BRS was positively related to cardiac output (r = ?0·48, P = 0·002) and stroke volume at peak exercise (r = 0·42, P = 0·007), and percent change increase in cardiac output (r = ?0·55, P = 0·0002) and stroke volume from rest to peak exercise (r = 0·41, P = 0·008). Furthermore, arterial BRS had modest but significant correlations with peak oxygen consumption (r = ?0·48, P = 0·002) and exercise duration (r = 0·35, P = 0·029), indicating that patients with better arterial BRS have better exercise capacity in patients with acute myocardial infarction. These results suggest that arterial BRS was linked to central and peripheral hemodynamic responses to exercise and hence, contributed to exercise capacity after acute myocardial infraction.     

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.     

Methodological aspects of the evaluation of endothelium-dependent vasodilatation in the human forearm

The present study, involving 56 healthy subjects from a health screening, was undertaken to address some methodological questions regarding the measurement of endothelial function using local intra-arterial infusions of metacholine (2 and 5 μg min^?1) to evaluate endothelium-dependent vasodilatation, and sodium nitroprusside (SNP, 5 and 10 μg min^?1) to evaluate endothelium-independent vasodilatation. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. The ratio of FBF during the highest dose of metacholine to FBF during the highest dose of SNP was used as an index of endothelial function. In 10 young volunteers the procedure was repeated after 2 h and again after 3 weeks in order to study short-term and long-term reproducibility of the method. Neither the vasodilatatory response to metacholine (r = 0·006) nor that to SNP (r = 0·08) was related to resting FBF. Neither the circumference nor the length of the arm was related to endothelial function (r = 0·01?0·11), as evaluated by the FBF on metacholine to nitroprusside ratio (mean 1·3 ± 0·3 SD). The use of a wrist cuff to exclude hand circulation, or not, did not influence the evaluation of endothelial function significantly. Maximal FBF after 3 min of arterial occlusion of the forearm was significantly related to blood flow during both metacholine (r = 0·53, P < 0·01) and nitroprusside infusion (r = 0·36, P < 0·05), but not to the FBF on metacholine to nitroprusside ratio (r = 0·01). The short-term and long-term reproducibility of FBF during vasodilatation with metacholine and SNP was good (r = 0·89?0·97, P < 0·001), while the individual measurements for resting FBF were less reproducible when repeated after 3 weeks (r = 0·34). In conclusion, endothelial function was not related to resting FBF, nor to the arm circumference or length. No major difference was seen whether endothelial function was evaluated with or without exclusion of the hand circulation. Maximal FBF during reactive hyperaemia was not related to endothelial function.     

Reduced preload elicits increased LV twist in healthy humans: an echocardiographic speckle-tracking study during lower body negative pressure

Background: In normal left ventricles (LV), counterclockwise rotation (CCR) and net twist angle (NTA) have shown important roles during ejection. We investigated the effect of reduced preload by lower body negative pressure (LBNP) on CCR and NTA. Methods and Results: Twelve healthy men were examined at rest, LBNP ?20 and ?40 mmHg. By two‐dimensional speckle‐tracking imaging, we measured rotation at four short‐axis levels: basal, papillary, sub‐papillary and apical. LV NTA was calculated as apex‐to‐base difference in rotation. Additionally, regional end‐diastolic (EDA) and end‐systolic area (ESA) were measured and regional area fraction (RAF) calculated [(EDA‐ESA)/EDA] × 100). From rest to LBNP ?40 mmHg, rotation at basal and papillary levels was unchanged. At sub‐papillary level, rotation increased from 3·2 ± 3·6 to 5·8 ± 4·7° (P<0·05), while apical rotation increased from 9·3 ± 3·4 to 12·8 ± 4·7° (P<0·05). Correspondingly, LV NTA increased for each load reduction by 1·6 ± 1·8° (P<0·05) and 4·2 ± 2·3° (P<0·05). RAF increased at sub‐papillary and apical levels from 57·6 ± 3·7 to 64·7 ± 8·8% and from 63·4 ± 8·8 to 74·8 ± 10·1%, respectively (P<0·05). From rest to LBNP ?40 mmHg, changes in rotation and RAF correlated significantly at sub‐papillary and apical levels (r = 0·94, P<0·01, and r = 0·63, P<0·05, respectively). Conclusions: Preload reduction in normal LV elicits increased systolic CCR and regional area fraction at sub‐papillary and apical levels as well as net twist angle. These findings might be of physiological importance to minimize reduction in stroke volume and maintain arterial blood pressure.     

Cardiac sympathetic activity is associated with inflammation and neurohumoral activation in patients with idiopathic dilated cardiomyopathy

Background: Idiopathic dilated cardiomyopathy (IDC) is characterized by sympathetic nervous overactivity, inflammation and neurohumoral activation; however, their interrelationships are poorly understood. Methods and results: We studied 99 patients with IDC (age 54 ± 1 years, left ventricular ejection fraction (EF) 40 ± 1%, maximum oxygen uptake (VO₂max) 20 ± 1 ml kg^?1 min^?2, mean ± SEM) by using ¹²³I‐metaiodobenzylguanidine (MIBG) imaging. MIBG washout and MIBG heart/mediastinum (H/M)‐ratio at 4 h postinjection were calculated. In addition, the plasma levels of interleukin (IL)‐6 and N‐terminal B‐type natriuretic peptide (NT‐proBNP) were measured. MIBG washout and MIBG H/M ratio had a significant correlation with IL‐6 (r = 0·42, P<0·001 and r = ?0·31, P<0·01) and NT‐proBNP (r = 0·48, P<0·001 and r = ?0·40, P<0·001). During a median follow‐up of 4·1 years, 20 patients (20%) had an adverse cardiac event (death, heart transplantation or application of biventricular pacemaker or implantable cardioverter–defibrillator). In these patients, MIBG washout was higher (53 ± 4 versus 40 ± 2%, P = 0·01) and H/M ratio lower (1·38 ± 0·04 versus 1·51 ± 0·02, P = 0·01) than in patients without an event. Conclusions: In dilated cardiomyopathy, myocardial sympathetic innervation and activity are related to inflammation and neurohumoral activation. These relationships are at least partly independent of left ventricular function and exercise capacity.     

Restoration of peak vascular conductance after simulated microgravity by maximal exercise

We sought to determine if (i) peak vascular conductance of the calf was reduced following prolonged exposure to simulated microgravity, and (ii) if maximal cycle ergometry performed at the end of microgravity exposure stimulated a restoration of peak calf vascular conductance. To do this, peak vascular conductance of the calf was recorded following ischaemic plantar flexion exercise to fatigue in seven men after 16 days of head-down tilt (HDT) under two conditions: (i) after one bout of maximal supine cycle ergometry completed 24 h prior to performance of ischaemic plantar flexion exercise, and (ii) in a control (no cycle ergometry) condition. Following HDT, peak vascular conductance was reduced in the control condition (0·38 ± 0·02 to 0·24 ± 0·02 ml 100 ml^?1 min^?1 mmHg^?1; P = 0·04), but was restored when subjects performed cycle ergometry (0·33 ± 0·05 to 0·28 ± 0·04 ml 100 ml^?1 min^?1 mmHg^?1; P = 0·46). After HDT, time to fatigue during ischaemic plantar flexion exercise was not different from pre-HDT 24 h after performance of exhaustive cycle ergometry (120 ± 24 vs. 122 ± 19 s), but was decreased in the control condition (116 ± 11 vs. 95 ± 8 s; P = 0·07). These data suggest that a single bout of maximal exercise can provide a stimulus to restore peak vascular conductance and maintain time to fatigue during performance of ischaemic plantar flexion exercise.     

The impact of short duration,high intensity exercise on cardiac troponin release

The aim of this study was to assess the appearance of cardiac troponins (cTnI and/or cTnT) after a short bout (30 s) of ‘all‐out’ intense exercise and to determine the stability of any exercise‐related cTnI release in response to repeated bouts of high intensity exercise separated by 7 days recovery. Eighteen apparently healthy, physically active, male university students completed two all‐out 30 s cycle sprint, separated by 7 days. cTnI, blood lactate and catecholamine concentrations were measured before, immediately after and 24 h after each bout. Cycle performance, heart rate and blood pressure responses to exercise were also recorded. Cycle performance was modestly elevated in the second trial [6·5% increase in peak power output (PPO)]; there was no difference in the cardiovascular, lactate or catecholamine response to the two cycle trials. cTnI was not significantly elevated from baseline through recovery (Trial 1: 0·06 ± 0·04 ng ml^?1, 0·05 ± 0·04 ng ml^?1, 0·03 ± 0·02 ng ml^?1; Trial 2: 0·02 ± 0·04 ng ml^?1, 0·04 ± 0·03 ng ml^?1, 0·05 ± 0·06 ng ml^?1) in either trial. Very small within subject changes were not significantly correlated between the two trials (r = 0·06; P>0·05). Subsequently, short duration, high intensity exercise does not elicit a clinically relevant response in cTnI and any small alterations likely reflect the underlying biological variability of cTnI measurement within the participants.     

Myocardial glutamate and alanine exchanges related to carbohydrate metabolism in patients with normal and stenotic coronary arteries

Summary. Myocardial exchanges of glutamate, alanine, glucose, lactate, free fatty acids (FFA) and oxygen in resting state were determined in nine subjects (controls) without and in 28 patients with coronary artery disease (CAD). Patients with CAD showed increased myocardial glutamate uptake (2·51±0·60 μmol/min) and alanine release (1·25±0·60μmol/min) compared to controls (glutamate uptake: 1·66±0·79 μmol/min; alanine release: 0·63±0·41 μmol/min). Myocardial glucose and lactate uptake was augmented in CAD patients, whereas FFA arterio-venous differences were decreased in patients with three-vessel-disease. The amount of glutamate taken up by the heart correlated positively to lactate uptake in all subjects (r= 0·84) and to external glucose utilization in patients with CAD (r= 0·72). Myocardial alanine release was positively related to glucose and lactate uptake in controls and in patients with only moderate CAD (one-vessel-disease). Glucose and FFA uptake correlated inversely in controls (r=0·84), but not in CAD patients. A tight relation between exchanges of glutamate/alanine and carbohydrate metabolism in human heart is demonstrated. The data suggest altered myocardial substrate exchange towards augmented carbohydrate utilization in CAD patients in resting state. The results agree with in vitro and animal studies suggesting extraction of glutamate from the circulation to be of importance for maintaining carbohydrate consumption in chronic ischaemic heart disease.     

Flow‐mediated dilation in the inactive limb following acute hypoxic exercise

The purpose of this study was to elucidate the effect of acute aerobic exercise performed under hypoxic conditions on flow‐mediated dilation (FMD) in the inactive limb. Seven males participated in the study. The subjects performed two submaximal leg cycling on a semirecumbent ergometer at the same relative intensity (60% peak oxygen uptake) in normoxia [inspired oxygen fraction (FIO₂) = 0·21] and hypoxia (FIO₂ = 0·12–0·13) for 30 min. The brachial artery diameter and blood velocity during exercise were measured via ultrasound, and the antegrade and retrograde shear rates were calculated. Before and 5, 30 and 60 min after exercise, brachial artery FMD was measured in normoxia. FMD was estimated as the percentage increase in peak diameter from the baseline diameter at prior occlusion (%FMD) and as the controlling changes in baseline diameter (the corrected‐%FMD). No difference in antegrade shear rate during exercise was detected between the normoxic and hypoxic conditions, whereas the retrograde shear rate was larger during hypoxic exercise. The %FMD decreased significantly at 5 min after exercise in both normoxia and hypoxia, and it returned to pre‐exercise levels within 60 min of recovery. Significant decreases in FMD at 5 min after exercise had disappeared when the baseline diameter was controlled using an analysis of covariance (the corrected‐%FMD). No significant differences were observed between the normoxic and hypoxic trials in the %FMD and corrected‐%FMD following exercise. These results suggest that hypoxia has no impact on endothelial function in the inactive limb following acute aerobic exercise.