Asthma and high-intensity interval training have no effect on clustered cardiometabolic risk or arterial stiffness in adolescents.

PURPOSE: Cardiometabolic risk, including arterial stiffness, is increasing in youth. Those with asthma are suggested to be particularly at risk of cardiovascular disease. Efficient and effective strategies are required to prevent the atherosclerotic process in youth. The purpose of this study was to investigate the effect of 6 months high-intensity interval training (HIIT) on cardiometabolic risk in youth with and without asthma. METHODS: 65 adolescents (31 mild asthma; 34 non-asthma) were recruited, 32 (16 asthma) of whom were randomly allocated to receive HIIT three times per week for 6 months. At baseline, mid-intervention, post-intervention and at a 3-month follow-up, anthropometric, metabolic and vascular determinants of cardiometabolic risk were assessed. Following principal component analysis (PCA), linear mixed models were used to assess the influence of asthma, HIIT and their interaction. RESULTS: Seven factors were identified which explained 88% of the common variance shared among the parameters. Those with asthma demonstrated lower arterial stiffness factor scores mid-intervention (P = 0.047) and lower cholesterol factor scores post-intervention (P = 0.022) but there was no effect of the intervention, or interaction effects, on any PCA-identified factor, at any time-point. HIIT was associated with a lower low-density lipoprotein and diastolic blood pressure at mid-intervention. DISCUSSION: Neither arterial stiffness nor clustered cardiometabolic risk are influenced by HIIT in adolescents with or without asthma, despite important changes in blood lipid and pressure profiles. Blood pressure, augmentation and pulse wave velocity should be considered physiologically distinct constructs and as potential markers of cardiovascular health.

HbA1c measurement and relationship to incident stroke.

AIMS: To determine the proportion of people with diabetes who have HbA1c measured, what proportion achieve an HbA1c level of < 58 mmol/mol (7.5%), the frequency of testing and if there was any change in HbA1c level in the year before and the year after an incident stroke. METHODS: This study used the Secure Anonymised Information Linkage (SAIL) databank, which stores hospital data for the whole of Wales and ~ 65% of Welsh general practice records, to identify cases of stroke in patients with diabetes between 2000 and 2010. These were matched against patients with diabetes but without stroke disease. We assessed the frequency of HbA1c testing and change in HbA1c in the first year after stroke. Estimation was made of the proportion of patients achieving an HbA1c measurement ≤ 58 mmol/mol (7.5%). RESULTS: There were 1741 patients with diabetes and stroke. Of these, 1173 (67.4%) had their HbA1c checked before their stroke and 1137 (65.3%) after their stroke. In the control group of 16 838 patients with diabetes but no stroke, 8413 (49.9%) and 9288 (55.1%) had their HbA1c checked before and after the case-matched stroke date, respectively. In patients with diabetes and stroke, HbA1c fell from 61-56 mmol/mol (7.7-7.3%) after their stroke (P < 0.001). Before the study, 55.0% of patients with stroke had an HbA1c ≥ 58 mmol/mol compared with 65.2% of control patients, these figures were 62.5% and 65.3% after the stroke. CONCLUSIONS: The frequency of diabetes testing was higher in patients who had experienced a stroke before and after their incident stroke compared with control patients but did not increase after their stroke. Glucose control improved significantly in the year after a stroke.

Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls.

AIMS: Clinical and observational studies have shown an increased risk of cardiovascular events and death associated with sulphonylureas versus metformin. However, it has never been determined whether this was due to the beneficial effects of metformin or detrimental effects of sulphonylureas. The objective of this study was therefore to compare all-cause mortality in diabetic patients treated first-line with either sulphonylurea or metformin monotherapy with that in matched individuals without diabetes. METHODS: We used retrospective observational data from the UK Clinical Practice Research Datalink (CPRD) from 2000. Subjects with type 2 diabetes who progressed to first-line treatment with metformin or sulphonylurea monotherapy were selected and matched to people without diabetes. Progression to all-cause mortality was compared using parametric survival models that included a range of relevant co-variables. RESULTS: We identified 78,241 subjects treated with metformin, 12,222 treated with sulphonylurea, and 90,463 matched subjects without diabetes. This resulted in a total, censored follow-up period of 503,384 years. There were 7498 deaths in total, representing unadjusted mortality rates of 14.4 and 15.2, and 50.9 and 28.7 deaths per 1000 person-years for metformin monotherapy and their matched controls, and sulphonylurea monotherapy and their matched controls, respectively. With reference to observed survival in diabetic patients initiated with metformin monotherapy [survival time ratio (STR) = 1.0], adjusted median survival time was 15% lower (STR = 0.85, 95% CI 0.81-0.90) in matched individuals without diabetes and 38% lower (0.62, 0.58-0.66) in diabetic patients treated with sulphonylurea monotherapy. CONCLUSIONS: Patients with type 2 diabetes initiated with metformin monotherapy had longer survival than did matched, non-diabetic controls. Those treated with sulphonylurea had markedly reduced survival compared with both matched controls and those receiving metformin monotherapy. This supports the position of metformin as first-line therapy and implies that metformin may confer benefit in non-diabetes. Sulphonylurea remains a concern.

Central arterial stiffness and diastolic dysfunction are associated with insulin resistance and abdominal obesity in young women but polycystic ovary syndrome does not confer additional risk.

STUDY QUESTION: Are arterial stiffness, carotid intima-media thickness and diastolic dysfunction increased in young women with polycystic ovary syndrome (PCOS) independently of the effects of obesity? SUMMARY ANSWER: Insulin resistance and central obesity are associated with subclinical cardiovascular dysfunction in young women, but a diagnosis of PCOS does not appear to confer additional risk at this age. WHAT IS KNOWN ALREADY: Some studies have shown that young women with PCOS may have increased measures of cardiovascular risk, including arterial stiffness, carotid intima-media thickness and myocardial dysfunction. However, it is difficult to establish how much of this risk is due to PCOS per se and how much is due to obesity and insulin resistance, which are common in PCOS and themselves associated with greater vascular risk. STUDY DESIGN, SIZE, DURATION: This cross-sectional study comprised 84 women with PCOS and 95 healthy volunteers, aged 16-45 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was conducted in a university hospital. Subjects underwent a comprehensive assessment of body composition (including computed tomography (CT) assessment of visceral fat; VF), measurements of arterial stiffness (aortic pulse wave velocity; aPWV), common carotid intima-media thickness (ccIMT), diastolic function (longitudinal tissue velocity; e':a') and endocrinological measures. A sample size of 80 in each group gave 80% power for detecting a difference of 0.45 m/s in aPWV or a difference of 0.25 in e':a'. MAIN RESULTS AND THE ROLE OF CHANCE: After adjustment for age and body mass index (BMI), PCOS subjects had a greater insulin response (insulin area under the curve-IAUC) following glucose challenge (adjusted difference [AD] 35 900 pmol min/l, P < 0.001) and higher testosterone (AD 0.57 nmol/l, P < 0.001) and high molecular weight adiponectin than controls (AD 3.01 µg/ml, P = 0.02), but no significant differences in aPWV (AD -0.13 m/s, P = 0.33), ccIMT (AD -0.01 mm, P = 0.13), or e':a' (AD -0.01, P = 0.86) were observed. After adjustment for age, height and central pulse pressure, e':a' and aPWV were associated with logVF and IAUC. ccIMT was not related to logVF. The relationships between e':a' or aPWV and insulin resistance were only partly attenuated by adjusting for logVF. There was no significant relationship between aPWV or e':a' and either testosterone or adiponectin. LIMITATIONS, REASONS FOR CAUTION: The study recruited young women meeting the Rotterdam criteria for PCOS diagnosis; hence our findings may not be generalizable to older patients or those meeting other definitions of the syndrome. Biochemical hyperandrogenism was based solely on measurement of total testosterone. Cases and controls were not matched in advance for age and BMI, although the influence of these variables on the cardiovascular outcome measures was adjusted for. WIDER IMPLICATIONS OF THE FINDINGS: This study shows that central arterial stiffness and diastolic dysfunction are not increased in young women with PCOS, whereas they are associated with both insulin resistance and central obesity. Obesity thus represents the greatest modifiable risk factor for cardiovascular disease in young women with PCOS and lifestyle measures which target weight reduction are critical. STUDY FUNDING/COMPETING INTERESTS: This study received no specific grant support from any funding body. The authors have no conflicts of interest to declare.

Chronic disease influences over 40 major life-changing decisions (MLCDs): a qualitative study in dermatology and general medicine.

BACKGROUND: Chronic disease not only impairs patients' psycho-social well-being but also influences major life-changing decisions (MLCDs). There is little information about the types of MLCDs affected and the long-term consequences. OBJECTIVES: The aims were to identify the MLCDs influenced by chronic disease, to define 'MLCD' and to suggest support strategies for patients taking MLCDs. METHODS: Adult dermatology patients explained how their chronic disease had influenced MLCDs in individual interviews. Adult patients from other medical specialities gave similar information by postal survey. NVivo8 software was used for qualitative analysis of data. Themes were categorized through a coding-recoding iterative process. RESULTS: There were 308 evaluable responses (male 55.2%; mean age = 51.8 years, mean disease duration = 19 years) from the 365 (55.7%) responses to the 655 patient invitations. These were used to generate themes to conceptualize 'MLCDs'. The most frequently reported MLCDs in the dermatology interviews concerned career choice (66%), job (58%), choice of clothing (54%), relationships (52%), education (44%), stopping swimming (34%), moving abroad (32%), not socializing (34%), wearing make-up (22%) and having children (22%). In the postal survey early retirement (40.6%), impact on job (29.4%), having children (24.8%), career choice (22.4%) and relationships (15.5%) were most commonly reported. The number of MLCDs reported by individuals was inversely related to age. Forty-one affected MLCD themes were grouped into 18 MLCD categories. A definition of MLCD was developed and strategies suggested to support patients. CONCLUSIONS: Chronic diseases influence a wide range of MLCDs. MLCDs are a novel domain in disease burden assessment. Clinicians' knowledge about this is important in patient management.

Quantitative detection of circulating endothelial cells in vasculitis: comparison of flow cytometry and immunomagnetic bead extraction.

BACKGROUND: Circulating endothelial cells (CECs) are biomarkers for endothelial cell (EC) injury and are quantified using immunomagnetic bead extraction (IBE), or flow cytometry (FC). Reports suggest that there is good agreement between these methods for CEC quantification. OBJECTIVES: We examined levels of agreement between these techniques in children with systemic vasculitis. METHODS: We added HUVEC or human pulmonary artery EC to whole blood to optimize FC gating strategies for EC. EC-optimized FC was then compared with IBE for CEC enumeration in 25 children with vasculitis and 20 healthy controls. RESULTS: Using Bland-Altman analysis, agreement between IBE and EC-optimized FC was poor in children with vasculitis (n = 25) and healthy controls (n = 20): IBE consistently detected higher values than the EC-optimized FC method: the mean difference between the two techniques was 60 CECs mL(-1), 95% CI +/-374 CECs mL(-1) (paired analyses of 45 individuals). Agreement was poorest for vasculitis patients: mean difference (IBE - EC-optimized FC) 120 CECs mL(-1), 95% CI +/-460 CECs mL(-1) (P = 0.018). We identified three reasons for this discrepancy: (i) sub-optimal FC gating parameters previously used for detecting CECs; (ii) inherent lack of sensitivity of FC compared with IBE for CEC rare event detection; and (iii) use of lysis buffers required for FC causing CEC lysis. CONCLUSIONS: There was poor agreement between EC-optimized FC and IBE for the quantification of CECs from children with active vasculitis and controls. We emphasize that in this clinical setting the two techniques are not directly comparable when comparing results obtained using these different methodologies.

Impact of aortic stenting on peripheral vascular function and daytime systolic blood pressure in adult coarctation.

OBJECTIVES: To determine the relation of ambulatory systolic blood pressure to aortic obstruction and more extensive vascular dysfunction, assessed by central aortic, peripheral conduit arterial and resistance vessel function. METHODS: 12 adults (5 native, 7 recoarctation) were studied before, and 2 weeks and 6 months after aortic stenting. Systolic blood pressure was measured during normal daily living by 24-hour ambulatory monitoring. Central aortic function was assessed by pulse wave analysis (augmentation index). Brachial artery flow-mediated dilatation and dilatation in response to 25 mug of sublingual glyceryl trinitrate was assessed by ultrasound to measure peripheral conduit arterial and resistance vessel function. Baseline vascular measures were compared with those of 12 matched controls. RESULTS: Patients had a higher augmentation index, impaired endothelium-dependent and -independent dilatation, and forearm vascular resistance (p<0.02). After successful gradient relief by stenting, daytime ambulatory systolic blood pressure (151 (134, 166) mm Hg vs 138 (130, 150) mm Hg, p = 0.01) and the augmentation index (26 (15, 34) vs 23 (13, 30), p = 0.03) fell progressively over 6 months, but did not completely normalise. Endothelium-dependent and -independent dilatation, and forearm vascular resistance remained unchanged and impaired. CONCLUSION: Relief of aortic obstruction is associated with improvement in central aortic function and results in reduction of daytime ambulatory systolic blood pressure. Peripheral vascular dysfunction, however, remains unchanged and may contribute to residual hypertension.

Endothelial cell function testing: how does the method help us in evaluating vascular status?

Vascular endothelial dysfunction describes a phenotype prone to atherogenesis and clinical complications of this disease process. Endothelium-dependent vasodilator function, reflecting local bioavailability of nitric oxide, can be measured clinically in the peripheral and coronary circulation and corresponds with other measures of endothelial biology including inflammatory status and thrombotic tendency. Although conventional risk factors are key determinants of endothelial dysfunction, many other factors, including the individual's genetic profile, also appear to exert important positive and negative functional influences. Thus, endothelial vasodilator function can be regarded as an integrated index of all atherogenic and atheroprotective factors acting on the vascular wall, reflecting underlying biology and inherent atherosclerotic risk. The potential clinical utility of endothelial vasomotor testing as a prognostic tool in risk assessment and for the monitoring of therapy requires further validation before recommending its wider routine use.

Coronary vasodilation and improvement in endothelial dysfunction with endothelin ET(A) receptor blockade.

The endothelium-derived peptide endothelin-1 (ET-1) causes vasoconstriction predominantly via smooth muscle ET(A) receptor activation. We hypothesized that ET(A) receptor inhibition would improve human coronary vascular function. We studied unobstructed coronary arteries of 44 patients with atherosclerosis or its risk factors. Epicardial diameter (D) and Doppler flow velocity were measured, and coronary vascular resistance (CVR) was calculated during intracoronary infusions of acetylcholine (ACH) and sodium nitroprusside (SNP), and during cold pressor testing, before and after a 60-minute intracoronary infusion of the ET(A) receptor antagonist BQ-123. BQ-123 dilated the coronary circulation; D increased by 5.6+/-1.0% (P<0.0001), and CVR fell by 12+/-3% (P<0.01). The D response to ACH, corrected for the SNP response, improved in segments that constricted with ACH at baseline (P=0.03), whereas segments that initially dilated with ACH did not change with BQ-123 (P=NS). Improvement in D and CVR responses to ACH with BQ-123 inversely correlated with baseline ACH responses (r=-0.44 [P=0.006] and r=-0.78 [P=0.001], respectively), indicating greater improvement in those with endothelial dysfunction. Similarly, cold pressor testing-mediated epicardial vasoconstriction (-2.0+/-1.1%) was reversed after BQ-123 (+1.0+/-0.7%), especially in dysfunctional segments (from -5.6+/-0.9% to +2.2+/-0.9%, P<0.001). There was no correlation between any risk factor and the response to BQ-123. An arteriovenous difference in ET-1 levels developed after BQ-123, which was consistent with enhanced cardiac clearance of ET-1, probably via ET(B) receptors. Thus, ET-1 acting via the ET(A) receptor contributes to basal human coronary vasoconstrictor tone and endothelial dysfunction. This suggests that ET(A) receptor antagonism may have therapeutic potential in the treatment of endothelial dysfunction and atherosclerosis.

Angiotensin type 1 receptor antagonism reverses abnormal coronary vasomotion in atherosclerosis.

OBJECTIVES: This study was performed to determine whether angiotensin type 1 (AT1) receptor inhibition improves abnormal coronary vasomotion and endothelial dysfunction in patients with atherosclerosis or its risk factors. BACKGROUND: Endothelial dysfunction, an early feature of atherosclerosis, contributes to abnormal vasomotion during stress. Angiotensin II may contribute to endothelial dysfunction in atherosclerosis. METHODS: In 25 patients, mean age 59 +/- 2 years, with atherosclerosis or its risk factors, we measured coronary vasomotion during flow-mediated dilation (FMD) in response to adenosine, cold pressor test (CPT) and exercise before and after AT1 receptor blockade with intracoronary losartan (5 mg). RESULTS: Losartan did not alter resting coronary vascular tone, but epicardial FMD improved from 5.6 +/- 1.5% to 8.9 +/- 1.8% (p = 0.02). Abnormal epicardial vasomotion during CPT and exercise also improved with losartan from -1.7 +/- 0.8% to 1.5 +/- 0.1% (p = 0.02) and -0.6 +/- 0.9% to 3.4 +/- 1.2% (p = 0.009), respectively. Improvement in epicardial vasomotion was most prominent in segments with baseline endothelial dysfunction evidenced as constriction during stress. Microvascular dilation during adenosine, an endothelium-independent response, was unchanged with losartan. CONCLUSIONS: Inhibition of the coronary vascular AT1 receptors in patients with atherosclerosis improves epicardial vasomotion during stress, probably by improving endothelial dysfunction. Whether AT1 receptor blockade will provide long-term therapeutic benefits in atherosclerosis needs further investigation.

Association between polymorphism in the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and atherosclerosis.

Fractalkine, a chemokine expressed by inflamed endothelium, induces leukocyte adhesion and migration via the receptor CX3CR1, and the CX3CR1 polymorphism V249I affects receptor expression and function. Here we show that this polymorphism is an independent risk factor for atherosclerotic coronary artery disease (CAD). Genotyping of the CX3CR1-V249I polymorphism was performed in a cohort of 339 white individuals who underwent cardiac catheterization (n=197 with and n=142 without CAD, respectively). In 203 patients, intracoronary acetylcholine 15 microg/min) and sodium nitroprusside (20 microg/min) were administered to test endothelium-dependent and -independent coronary vascular function, respectively. Change in coronary vascular resistance (DeltaCVR) was measured as an index of microvascular dilation. An association was observed between presence of the CX3CR1 I249 allele and reduced prevalence of CAD, independent of established CAD risk factors (odds ratio=0.54 [95% confidence interval, 0.30 to 0.96], P=0.03). Angiographic severity of CAD was also lower in these subjects (P=0.01). Furthermore, endothelium-dependent vasodilation was greater in these individuals compared with individuals homozygous for the CX3CR1-V249 allele (DeltaCVR during acetylcholine = -46+/-3% versus -36+/-3%, respectively, P=0.02), whereas DeltaCVR with sodium nitroprusside was similar in both groups (-55+/-2% versus -53+/-2%, P=0.45). The association between CX3CR1 genotype and endothelial function was independent of established risk factors and presence of CAD by multivariate analysis (P=0.02). Thus, the CX3CR1 I249 allele is associated with decreased risk of CAD and improved endothelium-dependent vasodilation. This suggests that CX3CR1 may be involved in the pathogenesis of CAD.

Characterization of endothelium-derived hyperpolarizing factor in the human forearm microcirculation.

The identity of endothelium-dependent hyperpolarizing factor (EDHF) in the human circulation remains controversial. We investigated whether EDHF contributes to endothelium-dependent vasomotion in the forearm microvasculature by studying the effect of K+ and miconazole, an inhibitor of cytochrome P-450, on the response to bradykinin in healthy human subjects. Study drugs were infused intra-arterially, and forearm blood flow was measured using strain-gauge plethysmography. Infusion of KCl (0.33 mmol/min) into the brachial artery caused baseline vasodilation and inhibited the vasodilator response to bradykinin, but not to sodium nitroprusside. Thus the incremental vasodilation induced by bradykinin was reduced from 14.3 +/- 2 to 7.1 +/- 2 ml x min(-1) x 100 g(-1) (P < 0.001) after KCl infusion. A similar inhibition of the bradykinin (P = 0.014), but not the sodium nitroprusside (not significant), response was observed with KCl after the study was repeated during preconstriction with phenylephrine to restore resting blood flow to basal values after KCl. Miconazole (0.125 mg/min) did not inhibit endothelium-dependent or -independent responses to ACh and sodium nitroprusside, respectively. However, after inhibition of cyclooxygenase and nitric oxide synthase with aspirin and NG-monomethyl-L-arginine, the forearm blood flow response to bradykinin (P = 0.003), but not to sodium nitroprusside (not significant), was significantly suppressed by miconazole. Thus nitric oxide- and prostaglandin-independent, bradykinin-mediated forearm vasodilation is suppressed by high intravascular K+ concentrations, indicating a contribution of EDHF. In the human forearm microvasculature, EDHF appears to be a cytochrome P-450 derivative, possibly an epoxyeicosatrienoic acid.

Antibodies to human heat-shock protein 60 are associated with the presence and severity of coronary artery disease: evidence for an autoimmune component of atherogenesis.

BACKGROUND: Antibodies to mycobacterial heat-shock protein (HSP) 65 have been reported to be associated with carotid artery thickening. We examined whether antibodies to human HSP60 are associated with the risk of coronary artery disease (CAD). METHODS AND RESULTS: Blood samples from 391 patients (62% men, mean age 57 years) being evaluated for CAD by coronary angiography were tested for IgG antibodies to human HSP60 by ELISA. We found that 75% of the study subjects had anti-HSP60 antibodies. The prevalence of CAD was increased in seropositive compared with seronegative patients (68% versus 49%, P:=0.0009). Mean titers of HSP60 antibodies were higher in CAD patients than in non-CAD patients (P:=0.008). No association between HSP60 antibodies and infection or inflammation was found. Importantly, HSP60 antibodies were related to disease severity. The prevalence of HSP60 antibodies was 76%, 80%, and 85% in patients with 1-, 2-, and 3-vessel disease, compared with 64% in patients without CAD (P: for trend=0.003). A similar association between increasing antibody titers and number of diseased vessels was also found (P:=0.03). Significant associations between antibodies to HSP60 and CAD severity persisted after adjustment for traditional risk factors by age, race, sex, smoking, diabetes, hypercholesterolemia, hypertension, and C-reactive protein levels. Adjusted OR for number of vessels diseased was 1.86 (95% CI 1.13 to 3.04). CONCLUSIONS: This is the first study demonstrating a significant association between human HSP60 antibodies and both the presence and severity of CAD.