Devina Bhowruth

Ethnic Differences in Carotid Intima-Media Thickness Between UK Children of Black African-Caribbean and White European Origin

Background and Purpose— UK black African-Caribbean adults have higher risks of stroke than white Europeans and have been shown to have increased carotid intima-media thickness (cIMT). We examined whether corresponding ethnic differences in cIMT were apparent in childhood and, if so, whether these could be explained by ethnic differences in cardiovascular risk markers. Methods— We conducted a 2-stage survey of 939 children (208 white European, 240 black African-Caribbean, 258 South Asian, 63 other Asian, 170 other ethnicity), who had a cardiovascular risk assessment and measurements of cIMT at mean ages of 9.8 and 10.8 years, respectively. Results— Black African-Caribbean children had a higher cIMT than white Europeans (mean difference, 0.014 mm; 95% CI, 0.008–0.021 mm; P<0.0001). cIMT levels in South Asian and other Asian children were however similar to those of white Europeans. Among all children, cIMT was positively associated with age, systolic and diastolic blood pressure and inversely with combined skinfold thickness and serum triglyceride. Mean triglyceride was lower among black African-Caribbeans than white Europeans; blood pressure and skinfold thickness did not differ appreciably. However, adjustment for these risk factors had little effect on the cIMT difference between black African-Caribbeans and white Europeans. Conclusions— UK black African-Caribbean children have higher cIMT levels in childhood; the difference is not explained by conventional cardiovascular risk markers. There may be important opportunities for early cardiovascular prevention, particularly in black African-Caribbean children.

Assessing the hydration status of children with chronic kidney disease and on dialysis: a comparison of techniques

Background Fluid balance is pivotal in the management of children with chronic kidney disease (CKD) and on dialysis. Although many techniques are available to assess fluid status, there are only a few studies for children, of which none have been comparable against cardiovascular outcome measures. Methods We performed a longitudinal study in 30 children with CKD5-5D and 13 age-matched healthy controls (71 measurements) to determine a correlation between optimal weight by bioimpedance spectroscopy (Wt-BIS) and clinical assessment (Wt-CA). The accuracy of Wt-BIS [relative overhydration (Rel-OH)] was compared against indicators of fluid status and cardiovascular measures. Results There was poor agreement between Wt-CA and Wt-BIS in children on dialysis (P = 0.01), but not in CKD5 or control subjects. We developed a modified chart to plot Rel-OH against systolic blood pressure (SBP) z-score for the appropriate representation of volume status and blood pressure (BP) in children. In total, 25% of measurements showed SBP >90th percentile but not with concurrent overhydration. Rel-OH correlated with peripheral pulse pressure (P = 0.03; R = 0.3), higher N-terminal pro-brain natriuretic peptide (P = 0.02; R = 0.33) and left ventricular end-diastolic diameter (P = 0.05; R = 0.38). Central aortic mean and pulse pressure significantly associated with the left ventricular end-diastolic diameter (P = 0.03; R = 0.47 and P = 0.01; R = 0.50, respectively), but not with Rel-OH. SBP was positively associated with pulse wave velocity z-score (P = 0.04). In total, 40% of children on haemodialysis and 30% on peritoneal dialysis had increased left ventricular mass index. Conclusions BIS provides an objective method for the assessment of hydration status in children on dialysis. We noted a marked discrepancy between BP and hydration status in children on dialysis that warrants further investigation.

Mitochondrial oxidative stress, endothelial function and metabolic control in patients with type II diabetes and periodontitis: A randomised controlled clinical trial

Background Periodontitis (PD) and type 2 diabetes (T2D) are characterized by increased mitochondrial oxidative stress production (mtROS), which has been associated with a greater risk of cardiovascular diseases (CVD). Intensive PD treatment (IPT) can significantly improve endothelial function and metabolic control, although the mechanisms remain unclear. We explored whether, in patients with PD and T2D, changes of mtROS are associated with improvement of endothelial function and metabolic control after IPT. Methods 51 patients with T2D and PD were enrolled in a single-blind controlled trial and randomised to either intensive (n = 27) or standard (CPT, n = 24) PD treatment. Levels of mtROS in peripheral blood mononuclear cells (PBMC) were measured using a FACS-based assay at baseline and 24 h, 1 week, 2 and 6 months after PD treatment. Inflammatory cytokines, CVD risk factors, metabolic control and endothelial function were assessed at baseline and 6 months after intervention. Results After 6 months from PD treatment, the IPT group had lower mtROS (in both the whole PBMC and lymphocytes), circulating levels of HbA1c, glucose, INF-γ, TNF-α (p < 0.05 for all), and improved endothelial function (p < 0.05) compared to the CPT group. There was an association between higher mtROS and lower endothelial function at baseline (r = −0.39; p = 0.01) and, in the IPT group, changes of mtROS were associated with changes of endothelial function (r = 0.41; p < 0.05). Conclusions Reduced mtROS is associated with improved endothelial function and accompanied by better metabolic control in patients with T2D and PD. mtROS could represent a novel therapeutic target to prevent CVD in T2D.

Systemic effects of periodontitis treatment in patients with type 2 diabetes: a 12 month, single-centre, investigator-masked, randomised trial

BACKGROUND Chronic inflammation is believed to be a major mechanism underlying the pathophysiology of type 2 diabetes. Periodontitis is a cause of systemic inflammation. We aimed to assess the effects of periodontal treatment on glycaemic control in people with type 2 diabetes. METHODS In this 12 month, single-centre, parallel-group, investigator-masked, randomised trial, we recruited patients with type 2 diabetes, moderate-to-severe periodontitis, and at least 15 teeth from four local hospitals and 15 medical or dental practices in the UK. We randomly assigned patients (1:1) using a computer-generated table to receive intensive periodontal treatment (IPT; whole mouth subgingival scaling, surgical periodontal therapy [if the participants showed good oral hygiene practice; otherwise dental cleaning again], and supportive periodontal therapy every 3 months until completion of the study) or control periodontal treatment (CPT; supra-gingival scaling and polishing at the same timepoints as in the IPT group). Treatment allocation included a process of minimisation in terms of diabetes onset, smoking status, sex, and periodontitis severity. Allocation to treatment was concealed in an opaque envelope and revealed to the clinician on the day of first treatment. With the exception of dental staff who performed the treatment and clinical examinations, all study investigators were masked to group allocation. The primary outcome was between-group difference in HbA1c at 12 months in the intention-to-treat population. This study is registered with the ISRCTN registry, number ISRCTN83229304. FINDINGS Between Oct 1, 2008, and Oct 31, 2012, we randomly assigned 264 patients to IPT (n=133) or CPT (n=131), all of whom were included in the intention-to-treat population. At baseline, mean HbA1c was 8·1% (SD 1·7) in both groups. After 12 months, unadjusted mean HbA1c was 8·3% (SE 0·2) in the CPT group and 7·8% (0·2) in the IPT group; with adjustment for baseline HbA1c, age, sex, ethnicity, smoking status, duration of diabetes, and BMI, HbA1c was 0·6% (95% CI 0·3-0·9; p<0·0001) lower in the IPT group than in the CPT group. At least one adverse event was reported in 30 (23%) of 133 patients in the IPT group and 23 (18%) of 131 patients in the CPT group. Serious adverse events were reported in 11 (8%) patients in the IPT group, including one (1%) death, and 11 (8%) patients in the CPT group, including three (2%) deaths. INTERPRETATION Compared with CPT, IPT reduced HbA1c in patients with type 2 diabetes and moderate-to-severe periodontitis after 12 months. These results suggest that routine oral health assessment and treatment of periodontitis could be important for effective management of type 2 diabetes. FUNDING Diabetes UK and UK National Institute for Health Research.

Short‐term heat therapy: sufficient stimulus for structural vascular adaptations?

The recent study investigating the effect of passive heat stress on vascular structure and function published by Brunt and co-workers in a recent issue of The Journal of Physiology (Brunt et al. 2016a) provides compelling evidence for the ability of heat therapy to exert improvements in multiple subclinical markers of cardiovascular disease, and has rightly received much positive interest in recent months. While the study appears carefully carried out and a number of measures of vascular function show physiologically plausible improvements, we have reservations over the rapid improvements reported in carotid intima-media thickness (cIMT) following treatment. The tests employed in the study included a wide range of arterial measures assessing structural changes (cIMT), functional changes (flow-mediated dilation; FMD), and composites of both (pulse-wave velocity; PWV). It is well known that changes in FMD and, to a lesser extent, PWV are largely determined by improvements in endothelial function, and numerous studies have previously shown the ability of numerous interventions (including heat stress) to induce rapid improvements in these responses. The haemodynamic changes accompanying these effects have also been investigated by a number of researchers – including ourselves – and a mechanistic basis for these adaptations therefore seems plausible (Tinken et al. 2009; Green et al. 2010; Carter et al. 2013; Chiesa et al. 2016). In contrast to FMD and PWV, however, changes in cIMT represent structural changes within the arterial wall which may occur in the intima, media, or both. Analysis of Fig. 4 from the current study suggests a remarkable decrease in cIMT from 0.43 mm to 0.38 mm following 8 weeks of heat therapy, yet no observable change in femoral intima-media thickness (fIMT) over the same time. We feel that this substantial change in cIMT may be unlikely for a number of reasons. Firstly, while it could be postulated that the decrease in cIMT observed here is due to atherosclerotic regression within the intimal layer, the use of young and healthy (albeit sedentary) participants in the study makes it unlikely that participants had any significant atherosclerotic burden to regress, as evidenced by cIMT values which are comparable to those from our laboratory in over 400 healthy young adults recruited from the Avon Longitudinal Study of Parents and Children (ALSPAC) (unpublished). Even in individuals with significant atherosclerotic burden and intimal thickening, such as those seen in heterozygous familial hypercholesterolaemia, regression of cIMT appears extremely difficult to achieve, as shown by a recent meta-analysis in which various high-dose statin treatments administered over periods of months reported a mean decrease in cIMT of only 0.025 mm (Masoura et al. 2011); that is, half of that observed by Brunt and co-workers. While intimal thickening in this population is unlikely, another component of the arterial wall that may respond to intervention is the underlying medial layer. Previously, the use of traditional ultrasound techniques has prevented the distinction between intimal and medial layers due to insufficient image resolution ( 12 MHz) resulting from limits in operating frequency. Using a very-high resolution ultrasound scanner operating at frequencies of up to 50 MHz, our group have recently investigated the determinants of intimal and medial thickening in a subset of 170 participants from the ALSPAC cohort, and have reported increases in IMT that appear to result from changes in the medial layer alone, with these changes related to increases in blood pressure and unrelated to serum lipid levels (Dangardt et al., 2016). While we note that a small decrease in blood pressure was observed in the current study, the extent and duration of this change seem insufficient for smooth muscle remodelling to occur. Secondly, previous research surrounding arterial adaptations to heat therapy have commonly focused on heat-induced increases in endothelial shear stress as the putative mechanisms underlying improvements in arterial function. We have previously shown that leg blood flow and shear rates during heating of the lower body are significantly increased (0.3 to 0.8 l min), with pro-atherogenic shear profiles decreased or even abolished (Chiesa et al. 2016). In contrast, increases in common carotid artery blood flow during moderate heat stress are minimal (Ogoh et al. 2013), with increases in skin blood flow partially offset by decreases in brain perfusion (Ogoh et al. 2013; Trangmar et al. 2017). With this in mind, it could be expected that greater vascular responses should have been observed in the lower limbs due to the greater stimulus, and encouragingly, with regards to beta-stiffness index this appears to be the case. However, despite these substantial improvements in compliance in this vessel, no effect was observed in fIMT, while in the carotid artery the opposite was true. There are a number of methodological considerations to consider when assessing whether the observed changes in cIMT over such a short time span may simply be an anomalous result. Firstly, the use of simple point-to-point caliper measurements – as appear to be have been used in the present study – are not recommended in cIMT guidelines (Stein et al. 2008), and where possible, semi-automated wall-tracking software covering a 1 cm portion of the vessel wall should be used to improve reproducibility. We appreciate that not all laboratories have access to this software; however, and while we note that the researchers have perhaps used an average of multiple wall measurements in order to overcome this, this analysis technique may have had an impact upon the results. Secondly, it is not clear from the methodology of the article whether the authors were blinded during analyses of cIMT, although it is again encouraging to note that this was the case for PWV analyses (Brunt et al. 2016b). Nevertheless, it should be emphasised for future studies that this is especially important if measurements are carried out manually, as unconscious analyser bias – while clearly inadvertent – remains a risk with this technique. In conclusion, we commend the authors on a well-conducted and insightful study that provides the first compelling evidence of heat therapy’s ability to simultaneously improve numerous measures of arterial function at multiple sites. The rapid changes observed in endothelial function and arterial stiffness are extremely promising, and may partially explain heat-induced improvements in symptoms and status previously documented in patients with peripheral arterial disease (Tei et al. 2007;

Intimal and medial arterial changes defined by ultra-high-frequency ultrasound: Response to changing risk factors in children with chronic kidney disease

Background Patients with chronic kidney disease (CKD) are exposed to both traditional ‘Framingham’ and uremia related cardiovascular risk factors that drive atherosclerotic and arteriosclerotic disease, but these cannot be differentiated using conventional ultrasound. We used ultra-high-frequency ultrasound (UHFUS) to differentiate medial thickness (MT) from intimal thickness (IT) in CKD patients, identify their determinants and monitor their progression. Methods Fifty-four children and adolescents with CKD and 12 healthy controls underwent UHFUS measurements using 55-70MHz transducers in common carotid and dorsal pedal arteries. Annual follow-up imaging was performed in 31 patients. Results CKD patients had higher carotid MT and dorsal pedal IT and MT compared to controls. The carotid MT in CKD correlated with serum phosphate (p<0.001, r = 0.42), PTH (p = 0.03, r = 0.36) and mean arterial pressure (p = 0.03, r = 0.34). Following multivariable analysis, being on dialysis, serum phosphate levels and mean arterial pressure remained the only independent predictors of carotid MT (R2 64%). Transplanted children had lower carotid and dorsal pedal MT compared to CKD and dialysis patients (p = 0.02 and p = 0.01 respectively). At 1-year follow-up, transplanted children had a decrease in carotid MT (p = 0.01), but an increase in dorsal pedal IT (p = 0.04) that independently correlated with annualized change in BMI. Conclusions Using UHFUS, we have shown that CKD is associated with exclusively medial arterial changes that attenuate when the uremic milieu is ameliorated after transplantation. In contrast, after transplantation intimal disease develops as hypertension and obesity become prevalent, representing rapid vascular remodeling in response to a changing cardiovascular risk factor profile.