Endothelium-dependent vasodilation in the skin microcirculation of patients with septic shock

The evidence for endothelial dysfunction in sepsis is mostly restricted to animal models. We investigated endothelial function in the skin microcirculation of eight patients hospitalized for septic shock in an intensive care unit (ICU). All patients required adrenergic support. Twelve hemodynamically stable ICU patients without sepsis who did not receive any vasoactive medication were used as controls. The two groups were of similar age and sex ratio. For additional reference, 16 healthy, nonsmoking subjects matched for age and sex to the first two groups were also studied. The evaluation of endothelial function was based on the comparison of skin blood flow responses to iontophoretically applied acetylcholine (Ach, an endothelium-dependent vasodilator) and sodium nitroprusside (SNP, an endothelium-independent vasodilator). Skin blood flow was measured on the volar face of the forearm using laser Doppler imaging. Before application of Ach or SNP, the mean baseline skin blood flow was below 100 perfusion units (PU) in all subjects and did not differ between groups. The maximal increase in blood flow elicited by both agents was significantly depressed in the patients with sepsis (Ach: 167 +/- 63 PU; SNP: 138 +/- 34 PU, mean +/- SD) compared with the ICU control patients (Ach: 291 +/- 135 PU, P < 0.05; SNP: 261 +/- 121 PU, P < 0.01) and the healthy, nonsmoking groups (Ach: 336 +/- 98 PU, P < 0.01; SNP: 304 +/- 81 PU, P < 0.01). The ratio of responses to Ach and SNP did not significantly differ between groups (septic: 1.22 +/- 0.40; ICU control 1.18 +/- 0.46, healthy, nonsmoking 1.12 +/- 0.24, P = 0.86). Thus, sepsis was not associated with a selective depression of the endothelium-dependent response. These results suggest that the capacity of the endothelium to produce signals for vasorelaxation remains intact in the skin microcirculation of patients with septic shock.     

Generalised wavelet analysis of cutaneous flowmotion during post-occlusive reactive hyperaemia in patients with peripheral arterial obstructive disease.

The purpose of the present study was to assess whether the generalised wavelet analysis (GWA) of the leg cutaneous laser Doppler (LD) flowmotion waves recorded during baseline (Bsl) and after skin post-occlusive hyperaemia (POH) can provide information on the leg cutaneous microcirculatory adaptation to stage II peripheral arterial obstructive disease (PAOD). With this aim the flowmotion was characterised in 20 healthy subjects (HS) and 20 stage II PAOD patients by GWA of LDF tracings during Bsl and POH test. The vascular endothelial and smooth muscle function was also evaluated exploring the arm skin vasodilatory response to iontophoretically delivered acetylcholine (Ach) and sodium nitroprusside (SNP) using LD. During Bsl there was no significant difference in leg skin perfusion between HS and PAOD patients (7.3+/-5.6 vs. 5.8+/-2.9 AU, respectively). PAOD patients revealed higher peak powers in the frequency interval of 0.007-0.02 Hz (120+/-82 vs. 85+/-62 AU(2)/Hz; P < 0.05), 0.02-0.06 Hz (116+/-128 vs. 63+/-48 AU(2)/Hz, respectively; P < 0.05) and 0.06-0.2 Hz (39+/-49 vs. 14+/-10 AU(2)/Hz; P < 0.05). These flowmotion frequencies are related to vascular endothelium activity, sympathetic activity and vessel wall myogenic activity, respectively. During POH the mean peak power of the flowmotion waves increased significantly (P < 0.05) in HS respect to Bsl with the only exception of the 0.02-0.06 Hz band. In the PAOD patients, compared to Bsl the amplitude of the flowmotion waves did not significantly change during POH. In addition, the PAOD patients presented an increased time from release to peak-flux (18.25+/-15.5 vs. 2.16+/-1.28 s, respectively; P < 0.05), an increased time from release to recovery of the basal perfusion (90.26+/-39.14 vs. 26.55+/-14.05 s, respectively; P < 0.05) and a lower slope of the POH curve (10+/-15 vs. 54+/-17 degrees , respectively; P < 0.05), compared with HS. The cutaneous arm vasodilatory response to Ach and to SNP was reduced in PAOD patients in comparison with HS (P < 0.001). In conclusion, our findings showed an increased amplitude of the frequency interval 0.007-0.02, 0.02-0.06 and 0.06-0.2 Hz during Bsl in PAOD patients which did not change during the POH test. All data suggest that in stage II PAOD patients the leg skin perfusion is not impaired during Bsl because of a compensatory mechanism related to increased endothelial, myogenic and sympathetic activities. However during reactive hyperaemia these mechanisms appear to be exhausted in accordance with the reduced vasoreactivity to Ach and SNP.     

The effect of glibenclamide on acetylcholine and sodium nitroprusside induced vasodilatation in human cutaneous microcirculation

Objective: K_ATP channels have an important regulatory role in resting vascular tone and during hypoxia. Their role in endothelium dependent and independent vasodilatation in human skin microcirculation is less known. Methods: We monitored the laser‐Doppler (LD) response in 14 healthy male volunteers on the skin of the forearm. In the case of endothelium dependent vasodilatation [acetylcholine (ACh) induced], a saline solution (used as control) or a solution of glibenclamide (K_ATP channel blocker) were randomly injected each into a distinct measurement site on different forearms followed by the iontophoresis of ACh. In the case of endothelium dependent vasodilatation with the inhibition of prostaglandin production, diclofenac (cyclooxygenase inhibitor) or the combination of diclofenac and glibenclamide were randomly injected each into a distinct measurement site on different forearms followed by the iontophoresis of ACh. In the case of endothelium independent vasodilatation [sodium nitroprusside (SNP) induced], a saline solution or glibenclamide were randomly injected each into a distinct measurement site on different forearms, iontophoresis of SNP followed. Results: Glibenclamide alone, diclofenac alone or the combination of glibenclamide and diclofenac reduced the LD flux values during rest and after ACh application (P<0·05). The reduction of LD flux in ACh mediated vasodilatation was greatest when using the combination of glibenclamide and diclofenac. In the case of SNP application, there was also a significantly lower LD flux rise for glibenclamide in comparison with the saline solution (P<0·05). Conclusions: K_ATP channels play an important role in human cutaneous vasodilatation induced by ACh and SNP.     

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.     

Effect of atorvastatin on impaired vascular function in healthy old men

OBJECTIVE: This study was initiated to examine the effect of cholesterol-lowering therapy with 40 mg atorvastatin on vascular function in healthy old and young men. METHODS: We selected healthy normolipidaemic, elderly subjects (n = 8, mean age 80.1 years) and young subjects (n = 7, mean age 21.8 years). All had a normal electrocardiograph and blood pressure, and signs or symptoms of cardiovascular disease were absent. The subjects were studied for 2 days, with 6 weeks of atorvastatin treatment in between. Forearm blood flow (FBF) was measured by computerized venous occlusion plethysmography upon intra-arterial infusion of acetylcholine (ACh; 30 and 90 ng/kg/min) and 5-hydroxytryptamine (5-HT; 0.3 and 0.9 ng/kg/min) as endothelium-dependent vasodilators, and sodium nitroprusside (SNP; 30 and 90 ng/kg/min) as an endothelium-independent vasodilator. RESULTS: At baseline, the mean absolute FBF in the elderly was 2.6 mL/min/100 mL and in the young 4.3 mL/min/100 mL tissue (P = 0.01). The mean serum total cholesterol levels were 5.2 and 3.8 mmol/L, respectively (P = 0.007). The endothelium-dependent vasodilatation induced by ACh and 5-HT was significantly lower in the elderly compared with the young (both P < 0.01), whereas the endothelium-independent vasodilatation induced by SNP was not significantly lower in the elderly compared with the young. Atorvastatin treatment decreased the serum total cholesterol level with a mean of 38 and 28% in the elderly and the young, respectively (P < 0.001). Impaired endothelium-dependent vasodilatation, however, was not modified (P > 0.65). CONCLUSIONS: Healthy old men have an impaired endothelium-dependent vascular response but this impairment is not restored by treatment with atorvastatin.     

Skin autofluorescence is increased in patients with carotid artery stenosis and peripheral artery disease

Advanced glycation end products (AGEs) have a pivotal role in atherosclerosis. We evaluated skin autofluorescence (SAF), a non-invasive measurement of tissue AGE accumulation, in patients with carotid artery stenosis with and without coexisting peripheral artery occlusive disease (PAOD). SAF was measured using the AGE Reader™ in 56 patients with carotid artery stenosis and in 56 age- and sex-matched healthy controls without diabetes, renal dysfunction or known atherosclerotic disease. SAF was higher in patients with carotid artery stenosis compared to the control group: mean 2.81 versus 2.46 (P = 0.002), but especially in the younger age group of 50–60 years old: mean 2.82 versus 1.94 (P = 0.000). Patients with carotid artery stenosis and PAOD proved to have an even higher SAF than patients with carotid artery stenosis only: mean 3.28 versus 2.66 (P = 0.003). Backward linear regression analysis showed that age, smoking, diabetes mellitus, renal function and the presence of PAOD were the determinants of SAF, but carotid artery stenosis was not. SAF is increased in patients with carotid artery stenosis and PAOD. The univariate and multivariate associations of SAF with age, smoking, diabetes, renal insufficiency and PAOD suggest that increased SAF can be seen as an indicator of widespread atherosclerosis.     

Respiratory muscle strength and muscle endurance are not affected by acute metabolic acidemia

Respiratory muscle fatigue in asthma and chronic obstructive lung disease (COPD) contributes to respiratory failure with hypercapnia, and subsequent respiratory acidosis. Therapeutic induction of acute metabolic acidosis further increases the respiratory drive and, therefore, may diminish ventilatory failure and hypercapnia. On the other hand, it is known that acute metabolic acidosis can also negatively affect (respiratory) muscle function and, therefore, could lead to a deterioration of respiratory failure. Moreover, we reasoned that the impact of metabolic acidosis on respiratory muscle strength and respiratory muscle endurance could be more pronounced in COPD patients as compared to asthma patients and healthy subjects, due to already impaired respiratory muscle function. In this study, the effect of metabolic acidosis was studied on peripheral muscle strength, peripheral muscle endurance, airway resistance, and on arterial carbon dioxide tension (PaCO₂). Acute metabolic acidosis was induced by administration of ammonium chloride (NH₄Cl). The effect of metabolic acidosis was studied on inspiratory and expiratory muscle strength and on respiratory muscle endurance. Effects were studied in a randomized, placebo‐controlled cross‐over design in 15 healthy subjects (4 male; age 33·2 ± 11·5 years; FEV₁ 108·3 ± 16·2% predicted), 14 asthma patients (5 male; age 48·1 ± 16·1 years; FEV₁ 101·6 ± 15·3% predicted), and 15 moderate to severe COPD patients (9 male; age 62·8 ± 6·8 years; FEV₁ 50·0 ± 11·8% predicted). An acute metabolic acidemia of BE –3·1 mmol.L^?1 was induced. Acute metabolic acidemia did not significantly affect strength or endurance of respiratory and peripheral muscles, respectively. In all subjects airway resistance was significantly decreased after induction of metabolic acidemia (mean difference –0·1 kPa.sec.L^?1 [95%‐CI: ?0·1 –?0·02]. In COPD patients PaCO₂ was significantly lowered during metabolic acidemia (mean difference –1·73 mmHg [?3·0 –?0·08]. In healthy subjects and in asthma patients no such effect was found. Acute metabolic acidemia did not significantly decrease respiratory or peripheral muscle strength, respectively muscle endurance in nomal subjects, asthma, or COPD patients. Metabolic acidemia significantly decreased airway resistance in asthma and COPD patients, as well as in healthy subjects. Moreover, acute metabolic acidemia slightly improved blood gas values in COPD patients. The results suggest that stimulation of ventilation in respiratory failure, by induction of metabolic acidemia will not lead to deterioration of the respiratory failure.     

Endothelium-dependent vasodilation and structural and functional changes in the cardiovascular system are dependent on age in healthy subjects

The aim of this study was to evaluate possible associations between endothelium-dependent vasodilatation (EDV) and cardiovascular structure and function. EDV could influence peripheral resistance and be affected by atherosclerosis and might thereby influence indices of cardiovascular structure and function. In a group of 31 apparently healthy men and 25 women (age range 20–69 years), EDV was evaluated by infusion of metacholine (4 μg min^–1), and endothelium-independent vasodilatation (EIDV) was assessed by nitroprusside infusion (SNP, 10 μg min^–1) in the brachial artery. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. Left ventricular (LV) geometry and function and the intima-media thickness in the carotid artery were assessed by ultrasonography. The stroke index to pulse pressure ratio was used to evaluate arterial compliance. Several indices of cardiovascular structure and function were found to be related to an index of endothelial function, the EDV to EIDV ratio. Furthermore, left ventricular mass (LVM), the atrio-ventricular plane displacement, E/A ratio, IVRT, the intima-media thickness of the carotid artery and arterial compliance were all significantly related to both EDV and EIDV in women. However, most indices of cardiovascular structure and function, as well as endothelial function, change with age and only the relation between LV diastolic function and endothelial function in men remained significant (P<0·05) after including age in multiple regression analysis. Age was related to both cardiovascular structure and function, as well as to endothelial function. Multiple regression analysis showed that ageing generally affects cardiovascular characteristics and endothelial function in parallel in these healthy subjects.     

Exercise blood pressure and endothelial dysfunction in hypertension

Background: Hypertensive patients with persistent endothelial dysfunction have adverse cardiovascular prognosis. However, current methods aimed to assess endothelial dysfunction in those patients who possess clinical applicability. We hypothesised that such individuals could potentially be identified by an exaggerated systolic blood pressure (BP) response to a submaximal exercise. Methods: We studied 22 male patients with essential hypertension who were categorised into two age‐matched groups depending on their exercise systolic BP (ExSBP) rise during the 3‐min exercise step test; the exaggerated ExSBP group [hyper‐responders (≥ 40 mmHg)] and the low ExSBP responder group [hypo‐responders (≤ 20 mmHg)]. Eleven healthy volunteers matched for age were used as control. Clinic and daytime ambulatory BP were assessed after 14 days of anti‐hypertensive treatment withdrawal, which were not significantly different between groups. Vascular reactivity in response to intra‐arterial infusions of acetylcholine, N^G‐monomethyl‐l ‐arginine (l ‐NMMA) and sodium nitroprusside was assessed using forearm venous occlusion plethysmography. Results: The hyper‐responder group had significantly less forearm vasodilatation to acetylcholine compared with the hypo‐responder group [percentage change in the forearm blood flow 125 (17) vs. 260 (28), mean (SEM); p < 0.001]. Similarly, the vasoconstrictive response to l ‐NMMA was significantly impaired in the hyper‐responder group in comparison to the hypo‐responder group [?30 (2) vs. ?45 (4); p < 0.05]. In contrast, the vascular response to sodium nitroprusside was not different between groups suggesting preserved endothelial‐independent vasodilatation. Conclusions: Despite similar ambulatory and office BP, the exaggerated ExSBP group had significantly worse endothelial function compared with the low ExSBP responder group. This simple and non‐invasive test may be useful in routine clinical practice to aid risk stratification in hypertensive patients.     

Evaluation of the dynamic cutaneous post-ischaemic hyperaemia and thermal response in elderly subjects and in an area at risk for pressure sores

Summary. The response of skin blood cell flux (SBF) to locally applied pressure was evaluated with the laser-Doppler technique in the areas of the sacrum and the gluteus maximus muscle of geriatric patients and healthy young and elderly subjects. The SBF over the sacrum stopped at a lower external skin pressure than over the gluteus muscle in all groups studied (P<0·05·0·001). The SBF at rest was lower among geriatric patients and over the sacrum, with men showing the lowest value (P<0·001). The initial slope of the SBF curve and the peak SBF during the post-occlusive reactive hyperaemia (PRH) were lower among geriatric patients compared to younger healthy subjects (P<0·05·0·01) over both areas studied. During the last part of the PRH response rhythmic oscillations started, known as vasomotion. The mean skin temperature at rest was higher over the sacrum (P<0·001) than over the gluteus area, but no difference was found between the groups. The temperature increase during the PRH was larger over the gluteus muscle (P<0·01) than over the sacrum area in the healthy subjects. Among the patients the temperature increase was larger over the gluteus only during the first half of the PRH, after which the temperature increased most over the sacrum. It is concluded that SBF and skin temperature show different responses in microvascular reactivity to external pressure in elderly vs. younger subjects and also between sexes. The described technique may be useful in clinical practice for predicting the risk of pressure sores in different areas and subjects.     

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.     

Feasibility and tolerability of probiotics for prevention of antibiotic‐associated diarrhoea in hospitalized US military veterans

Background: Probiotics may be efficacious for the prevention of antibiotic‐associated diarrhoea. The tolerability and acceptability of probiotics in an elderly US veteran population has not been assessed. Purpose: To undertake a randomized trial to determine the tolerability and acceptability of a probiotic, Florajen^® in an elderly population with multiple comorbidities. Methods: Pilot randomized double‐blind trial comparing a probiotic, Florajen^® to placebo for the prevention of antibiotic‐associated diarrhoea in elderly hospitalized patients receiving antibiotics. Results: Forty patients were enrolled and randomized. Antibiotic‐associated diarrhoea occurred in 6/16 (37%) in the placebo group and 4/23 (17%) patients in the Florajen^® group, (RR 1·63, 95% CI 0·73–3·65, P = 0·15). Florajen^® was well tolerated in the study population with no major side effects that necessitated discontinuation. Conclusions: In this pilot study, Florajen^® was well tolerated in an elderly population, all of whom were taking several other medications. A larger study is needed to determine the effect of Florajen^® on antibiotic‐associated diarrhoea and Clostridium difficile infection.     

Non-invasive assessment of endothelial function - relation between vasodilatory responses in skin microcirculation and brachial artery

OBJECTIVE: To compare different non-invasive methods for determination of human endothelial function in peripheral circulation. DESIGN: Observational, cross-sectional study in 39 healthy subjects (21 females, age 17-56 years). SETTING: Vascular research laboratory at university hospital. METHODS: Laser Doppler (LD) flowmetry was used to compare skin microvascular perfusion changes during postocclusive reactive hyperaemia with those induced by iontophoretic administration of acetylcholine (ACh), an endothelial-dependent vasodilator. LD measurements were compared with ultrasonographic measurements of postocclusive flow-mediated dilatation (FMD) in the brachial artery (n = 21). RESULTS: Local ACh induced a larger and more sustained skin perfusion increase than reactive hyperaemia after 4 min of regional arterial occlusion (P<0.001). A significant correlation was found between the magnitude of ACh-induced vasodilatation and peak reactive hyperaemia, both in absolute (r = 0.62, P<0.001) and relative terms (r = 0.58, P<0.001). A correlation was also found between brachial artery FMD and the magnitude of ACh-induced skin perfusion increase (r = 0.43, P<0.05) but not between FMD and reactive hyperaemia. CONCLUSION: Endothelial function, an early marker of cardiovascular risk, can be non-invasively assessed and graded by LD and FMD-measurements and despite inherent differences, both methods do correlate.     

Impaired coronary artery distensibility is an endothelium‐dependent process and is associated with vulnerable plaque composition

Coronary endothelial‐dependent microvascular dysfunction, an early reversible stage of coronary artery disease (CAD), is associated with poor clinical outcome. The current study investigated whether coronary artery distensibility index (CDI) is associated with: (i) coronary endothelial‐dependent microvascular dysfunction and (ii) vulnerable plaque composition among subjects with non‐obstructive CAD. Seventy‐four subjects with non‐obstructive CAD (luminal stenosis <30%) were studied. In 20 subjects with and without coronary endothelial‐dependent microvascular dysfunction, coronary flow reserve (CFR) of target segment during intracoronary (IC) infusion of acetylcholine (Ach) and bolus injection of adenosine as well as CDI at rest of corresponding target segment were measured. In 54 subjects, plaque compositions and CDI at rest of 154 non‐obstructive coronary segments as well as proximal segment without disease were measured by intravascular ultrasound (IVUS). CDI was defined as: [(Early‐diastolic cross‐sectional‐area (CSA) – End‐diastolic CSA of target segment)/(end‐diastolic CSA of target segment × coronary‐pulse‐pressure) × 10³]. There is a direct association between endothelial dysfunction and impaired CDI of a coronary segment both in the given coronary segment and corresponding microvessels in which a strong agreement between CDI and CFR Ach (r² = 0·85, P = 0·0001) was observed. Multivariable regression‐analysis showed that CDI was an independent predictor of the vulnerable plaque characteristics. The risk of impaired CDI was 125% higher in segments with necrotic core and 60% higher in segments with fibrofatty components as compared to normal segments (P = 0·001). In conclusions, the current study reveals that impaired CDI is an endothelial‐dependent process of both given coronary segment and corresponding microvessels and is associated with vulnerable plaque composition.     

The effects of maximal treadmill graded exercise testing on haemorheological, haemodynamic and flow cytometry platelet markers in patients with systolic or diastolic heart failure

Background Acute exercise has been associated with activation of thrombosis, and this risk may be accentuated in patients with heart failure. Given the relation of platelets to atherothrombosis, we tested the hypothesis that acute exercise would adversely affect platelet indices and platelet activation markers in patients with systolic and diastolic heart failure. Materials and methods We studied 20 patients with systolic heart failure (17 men, 3 women; mean age 64 ± 10 years, all with ejection fraction (EF) ≤ 40%) and 20 patients with diastolic heart failure (14 men, 6 women; mean age 64 ± 8 years, mean EF = 66%) who were exercised to maximal intensity, who were compared to 13 healthy controls (6 men, 7 women; mean age 60 ± 4 years, mean EF = 73%). We measured platelet indices (platelet volume, mass and component) and platelet activation markers (platelet‐bound CD62P%G, CD63%G and CD40L%G using flow cytometry, as well as plasma sCD40L and soluble P‐selectin (sP‐sel) levels). Results Baseline Mean Platelet Volume (MPV), sP‐sel, CD40L%G and CD63%G levels were significantly higher in patients with systolic and diastolic heart failure, when compared with controls. The mean exercise duration and VO₂ peak in patients with systolic and diastolic heart failure were not significantly different, but lower than that seen in healthy controls. Following exercise, mean haematocrit, CD62P%G, and CD63%G significantly increased in all three subject groups (all P < 0·05). The proportional change in CD62P%G and CD63%G were not significantly different between healthy controls and heart failure patients (P > 0·05). Conclusion Acute maximal graded exercise increases platelet activation markers, with no disproportionate differences between heart failure patients and healthy controls, despite the former group having a lower exercise tolerance and VO₂ peak.     

Comparing the cumulative incidences of add‐on therapy among the major antihypertensive classes in 2531 Asian patients: a cohort study

Background: Published literature addressing the efficacy of different antihypertensive drug classes among Asian patients is scarce. Methods: This cohort study included all patients prescribed their first‐ever antihypertensive monotherapy without concomitant use of chronic medications in two primary care clinics in Hong Kong during 1990–2002. The incidence of add‐on therapy within 48 weeks because of suboptimal blood pressure control was evaluated and compared among different age and gender groups. Results and discussion: Among the 2531 patients, the incidence of add‐on therapy among users of angiotensin converting enzyme inhibitors (ACEI) was highest in young females (31·1%, 95% CI 22·2%, 40·0%, P < 0·001) and elderly females (18·0%, 95% CI 11·3%, 24·7%, P = 0·049) as compared with thiazide diuretics, beta‐blockers and calcium channel blockers. The incidence of add‐on therapy among young males (20·3%, 95% CI 11·1%, 29·5%; P > 0·50) and elderly males (12·5%, 95% CI 3·8%, 21·2%) was also highest with the ACEI than other drug classes although statistical significance was not reached. Conclusion: The incidence of add‐on therapy among first‐time antiypertensives appear to be significantly different between drug classes. This deserves further investigation.     

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.     

Predicted maximal heart rate for upper body exercise testing

Age‐predicted maximal heart rate (HR_MAX) equations are commonly used for the purpose of prescribing exercise regimens, as criteria for achieving maximal exertion and for diagnostic exercise testing. Despite the growing popularity of upper body exercise in both healthy and clinical settings, no recommendations are available for exercise modes using the smaller upper body muscle mass. The purpose of this study was to determine how well commonly used age‐adjusted prediction equations for HR_MAX estimate actual HR_MAX for upper body exercise in healthy young and older adults. A total of 30 young (age: 20 ± 2 years, height: 171·9 ± 32·8 cm, mass: 77·7 ± 12·6 kg) and 20 elderly adults (age: 66 ± 6 years, height: 162 ± 8·1 cm, mass: 65·3 ± 12·3 kg) undertook maximal incremental exercise tests on a conventional arm crank ergometer. Age‐adjusted maximal heart rate was calculated using prediction equations based on leg exercise and compared with measured HR_MAX data for the arms. Maximal HR for arm exercise was significantly overpredicted compared with age‐adjusted prediction equations in both young and older adults. Subtracting 10–20 beats min^?1 from conventional prediction equations provides a reasonable estimate of HR_MAX for upper body exercise in healthy older and younger adults.     

Reproducibility of orthostatic changes in cerebral oxygenation in healthy subjects aged 70 years or older

In the elderly, standing can frequently be accompanied by blood pressure (BP) changes and cerebral symptoms such as dizziness, fall, or even syncope, but this may vary from day‐to‐day. Therefore, we aimed to investigate the reproducibility of orthostatic responses of cerebral cortical oxygenation and systemic haemodynamics in elderly subjects. In 27 healthy elderly subjects (age 70–84 years), changes in systolic BP (SBP), diastolic BP (DBP), heart rate (HR) and stroke volume (SV) were continuously monitored by Finapres (Finger Arterial Pressure), and changes in oxyhaemoglobin ([O₂Hb]) and deoxyhaemoglobin ([HHb]) concentrations were continuously measured over the right frontal cortex by near infrared spectroscopy (NIRS) during supine rest and 10 min of active standing on two separate occasions. SBP and DBP increased by 6·7 ± 15·4 mmHg (P<0·05, mean ± SD) and 8·2 ± 6·4 mmHg (P<0·01), respectively, whereas HR increased by 9·5 ± 5·0 bpm (P<0·01) and SV decreased by –8·3 ± 7·4 ml (P<0·01) during standing on the first occasion. [O₂Hb] decreased by –3·9 ± 2·9 μmol l^–1 (P<0·01), while [HHb] increased by 1·8 ± 2·2 μmol l^–1 (P<0·01). Group‐averaged orthostatic changes in cortical oxygenation and systemic haemodynamics were very similar on the two occasions, although an intraindividual variation was found. Cortical oxygenation changes were not accompanied by severe cerebral symptoms. Active standing induced reproducible group‐averaged frontal cortical oxygenation declines in healthy elderly subjects, although an intraindividual day‐to‐day variability was present, possibly related to the variability of orthostatic BP responses. These findings indicate that cerebral autoregulation fails to compensate completely for postural changes in elderly subjects, which might predispose elderly subjects to ischaemic cerebral symptoms.     

Development of new peripheral arterial occlusive disease in patients with type 2 diabetes during a mean follow-up of 11 years

OBJECTIVE: To assess the occurrence and development of new peripheral arterial occlusive disease (PAOD), its risk factors, and the outcome in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 130 type 2 diabetic patients (mean age 58 years) were examined at baseline and after a mean follow-up of 11 years (range 7-14). The ankle-brachial index (ABI) and toe-brachial index were used to detect PAOD. Blood and urine samples were taken at baseline, and a history of cardiovascular events was recorded during follow-up. RESULTS: PAOD was diagnosed in 21 (16%) patients at baseline. During follow-up, 21 of 89 (24%) patients developed new PAOD. There were 29 patients who died, 21 (72%) of them from cardiovascular disease. Patients with PAOD suffered an excess mortality compared with patients without PAOD (58 vs. 16%; P < 0.001). Logistic regression analysis showed that PAOD at baseline was associated with age, duration of diabetes, smoking, and urinary albumin excretion rate. Patients who developed new PAOD during follow-up had higher serum LDL cholesterol concentrations and lower HDL cholesterol concentrations and were older than the patients who remained free of PAOD. CONCLUSIONS: Objectively measured PAOD is frequent in type 2 diabetic patients. It presents the early clinical signs of atherosclerosis and is strongly associated with cardiovascular death. The risk factor pattern for PAOD was different at baseline and after a mean follow-up of 11 years. We consider routine ABI measurements and modification of risk factors necessary also in patients with asymptomatic PAOD.