Scott T. Chiesa

Recent developments in near-infrared spectroscopy (NIRS) for the assessment of local skeletal muscle microvascular function and capacity to utilise oxygen

Purpose of review Continuous wave near infrared spectroscopy (CW NIRS) provides non-invasive technology to measure relative changes in oxy- and deoxy-haemoglobin in a dynamic environment. This allows determination of local skeletal muscle O2 saturation, muscle oxygen consumption (V˙O2) and blood flow. This article provides a brief overview of the use of CW NIRS to measure exercise-limiting factors in skeletal muscle. Recent findings NIRS parameters that measure O2 delivery and capacity to utilise O2 in the muscle have been developed based on response to physiological interventions and exercise. NIRS has good reproducibility and agreement with gold standard techniques and can be used in clinical populations where muscle oxidative capacity or oxygen delivery (or both) are impaired. CW NIRS has limitations including: the unknown contribution of myoglobin to the overall signals, the impact of adipose tissue thickness, skin perfusion during exercise, and variations in skin pigmentation. These, in the main, can be circumvented through appropriate study design or measurement of absolute tissue saturation. Summary CW NIRS can assess skeletal muscle O2 delivery and utilisation without the use of expensive or invasive procedures and is useable in large population-based samples, including older adults.

ACE Inhibitors and Statins in Adolescents with Type 1 Diabetes

Background Among adolescents with type 1 diabetes, rapid increases in albumin excretion during puberty precede the development of microalbuminuria and macroalbuminuria, long‐term risk factors for renal and cardiovascular disease. We hypothesized that adolescents with high levels of albumin excretion might benefit from angiotensin‐converting–enzyme (ACE) inhibitors and statins, drugs that have not been fully evaluated in adolescents. Methods We screened 4407 adolescents with type 1 diabetes between the ages of 10 and 16 years of age and identified 1287 with values in the upper third of the albumin‐to‐creatinine ratios; 443 were randomly assigned in a placebo‐controlled trial of an ACE inhibitor and a statin with the use of a 2‐by‐2 factorial design minimizing differences in baseline characteristics such as age, sex, and duration of diabetes. The primary outcome for both interventions was the change in albumin excretion, assessed according to the albumin‐to‐creatinine ratio calculated from three early‐morning urine samples obtained every 6 months over 2 to 4 years, and expressed as the area under the curve. Key secondary outcomes included the development of microalbuminuria, progression of retinopathy, changes in the glomerular filtration rate, lipid levels, and measures of cardiovascular risk (carotid intima–media thickness and levels of high‐sensitivity C‐reactive protein and asymmetric dimethylarginine). Results The primary outcome was not affected by ACE inhibitor therapy, statin therapy, or the combination of the two. The use of an ACE inhibitor was associated with a lower incidence of microalbuminuria than the use of placebo; in the context of negative findings for the primary outcome and statistical analysis plan, this lower incidence was not considered significant (hazard ratio, 0.57; 95% confidence interval, 0.35 to 0.94). Statin use resulted in significant reductions in total, low‐density lipoprotein, and non–high‐density lipoprotein cholesterol levels, in triglyceride levels, and in the ratio of apolipoprotein B to apolipoprotein A1, whereas neither drug had significant effects on carotid intima–media thickness, other cardiovascular markers, the glomerular filtration rate, or progression of retinopathy. Overall adherence to the drug regimen was 75%, and serious adverse events were similar across the groups. Conclusions The use of an ACE inhibitor and a statin did not change the albumin‐to‐creatinine ratio over time. (Funded by the Juvenile Diabetes Research Foundation and others; AdDIT ClinicalTrials.gov number, NCT01581476.)

Assessing the causal role of body mass index on cardiovascular health in young adults: Mendelian randomization and recall-by-genotype analyses

Background Mendelian randomization (MR) studies of body mass index (BMI) and cardiovascular health in mid-to-late life suggest causal relationships, but the nature of these has not been explored systematically at younger ages. Using complementary MR and recall-by-genotype (RbG) methodologies, our objective was to estimate the causal effect of BMI on detailed measures of cardiovascular health in a population of young healthy adults. Methods and Findings Data from the Avon Longitudinal Study of Parents and Children were used. For MR analyses, a genetic risk score (GRS) comprising 97 independent single nucleotide polymorphisms (SNPs) and constructed using external weighting was used as an instrument to test the causal effect of each unit increase in BMI (kg/m2) on selected cardiovascular phenotypes measured at age 17 (N=7909). An independent enriched sample from the same cohort participated in a RbG study at age 21, which enabled more detailed cardiovascular phenotyping (N=418; 191/227 from the lower/upper ∼30% of a genome-wide GRS distribution predicting variation in BMI). The causal effect of BMI on the additional cardiovascular phenotypes was assessed by comparing the two recalled groups. Difference in mean BMI between RbG groups was 3.85kg/m2 (95% CI: 2.53, 4.63; P=6.09×1011). In both MR and RbG analyses, results indicated that higher BMI causes higher blood pressure (BP) and left ventricular mass (indexed to height2.7, LVMI) in young adults (e.g. difference in LVMI per kg/m2 using MR: 1.07g/m2.7; 95% CI: 0.62, 1.52; P=3.87×10−06 and per 3.58kg/m2 using RbG: 1.65g/m2.7 95% CI: 0.83, 2.47; P=0.0001). Additionally, RbG results indicated a causal role of higher BMI on higher stroke volume (SV; difference per 3.58kg/m2: 1.49ml/m2.04; 95% CI: 0.62, 2.35; P=0.001) and cardiac output (CO; difference per 3.58kg/m2: 0.11l /min/m1.83; 95% CI: 0.03, 0.19; P=0.01). Neither analysis supported a causal role of higher BMI on heart rate. Conclusions Complementary MR and RbG causal methodologies, together with a range of appropriate sensitivity analyses, showed that higher BMI is likely to cause worse cardiovascular health, specifically higher BP and LVMI, even in youth. These consistent results support efforts to prevent or reverse obesity in the young.

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;

Clustering of cardio-metabolic risk factors in parents of adolescents with type 1 diabetes and microalbuminuria

To evaluate the association between a clustering of cardio‐metabolic risk factors in parents and the development of microalbuminuria (MA) in their offspring with childhood‐onset type 1 diabetes (T1D).

Statins in Peripheral Arterial Disease

Peripheral arterial disease (PAD) is a common atherosclerotic condition affecting the lower extremities. PAD patients share similar cardiovascular risk factors to coronary artery disease patients and suffer from increased cardiovascular morbidity and mortality. Statins have been widely used in coronary artery disease patients but have been underused in patients with PAD. In the current review, we present data, which support the beneficial role of statins in both reducing cardiovascular events and improving symptom-related outcomes in PAD patients. Alongside their lipid lowering effects, their pleiotropic actions are also discussed. Recent guidelines, which strongly recommend the administration of statins in PAD patients, are also presented.

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.

Renal and Cardiovascular Risk According to Tertiles of Urinary Albumin-to-Creatinine Ratio: The Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT)

OBJECTIVE Baseline data from the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT) indicated that tertiles of urinary albumin-to-creatinine ratios (ACRs) in the normal range at age 10–16 years are associated with risk markers for diabetic nephropathy (DN) and cardiovascular disease (CVD). We aimed to determine whether the top ACR tertile remained associated with DN and CVD risk over the 2–4-year AdDIT study. RESEARCH DESIGN AND METHODS One hundred fifty adolescents (mean age 14.1 years [SD 1.6]) with baseline ACR in the upper tertile (high-ACR group) recruited to the AdDIT trial, who remained untreated, and 396 (age 14.3 years [1.6]) with ACR in the middle and lower tertiles (low-ACR group), who completed the parallel AdDIT observational study, were evaluated prospectively with assessments of ACR and renal and CVD markers, combined with carotid intima-media thickness (cIMT) at baseline and end of study. RESULTS After a median follow-up of 3.9 years, the cumulative incidence of microalbuminuria was 16.3% in the high-ACR versus 5.5% in the low-ACR group (log-rank P < 0.001). Cox models showed independent contributions of the high-ACR group (hazard ratio 4.29 [95% CI 2.08–8.85]) and HbA1c (1.37 [1.10–1.72]) to microalbuminuria risk. cIMT change from baseline was significantly greater in the high- versus low-ACR group (mean difference 0.010 mm [0.079], P = 0.006). Changes in estimated glomerular filtration rate, systolic blood pressure, and hs-CRP were also significantly greater in the high-ACR group (P < 0.05). CONCLUSIONS ACR at the higher end of the normal range at the age of 10–16 years is associated with an increased risk of progression to microalbuminuria and future CVD risk, independently of HbA1c.

Hydration and the human brain circulation and metabolism

1Centre for Sports Medicine and Human Performance, Brunel University London, United Kingdom. 2Centre for Sport, Health and Applied Science, St Mary’s University, Twickenham, United Kingdom. 3Institute of Cardiovascular Science, University College London, United Kingdom. 4Center for Infection and Immunity Research, St George’s University of London, United Kingdom. 5Department of Anaesthesia, The Copenhagen Muscle Research Centre, Rigshospitalet, University of Copenhagen, Denmark.