Analysis of Predictive Information From Biomarkers Added to Clinical Models of Preeclampsia: Consideration of PAPP-A2, Activin A, and sFlt-1:PlGF Ratio.

BACKGROUND: Preeclampsia remains a major cause of maternal and fetal adverse outcomes in pregnancy; however, accurate and universally acceptable predictive tools remain elusive. We investigated whether a panel of biomarkers could improve risk prediction for preeclampsia when measured at various pregnancy time points. METHODS: In this prospective cohort study, 192 women with first-trimester high-risk singleton pregnancies were consecutively recruited from tertiary obstetrics clinics in Montréal, Canada. Clinical information (height, pre-pregnancy weight, personal and family medical history, medication use) was collected at baseline. Blood pressure was measured and blood samples collected at each trimester to quantify soluble Fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), pregnancy-associated plasma protein A2 (PAPP-A2), PAPP-A, activin A, inhibin A, follistatin, and glycosylated fibronectin. A random-effects hierarchic logistic regression model was used to relate change in biomarker levels to incidence of preeclampsia. RESULTS: When added to a clinical model composed of maternal age, pre-pregnancy body mass index, race, and mean arterial pressure, a positive third-trimester result for both PAPP-A2 and activin A had a better positive predictive value than the sFlt-1:PlGF ratio added to the clinical model (91.67% [95% confidence interval (CI) 78.57%-100%] vs 66.67% [57.14%-100%]), while maintaining a comparable high negative predictive value (97.69% [95% CI 95.34%-100%] vs 96.00% [92.19%-99.21%]). CONCLUSIONS: Whereas the third-trimester sFlt-1:PlGF ratio can predict short-term absence of preeclampsia, PAPP-A2 and activin A had both high positive and negative predictive values and therefore could serve as biomarkers to predict the occurrence (and absence) of preeclampsia; these findings will be validated in future studies.

Association Between Patient Factors and the Effectiveness of Wearable Trackers at Increasing the Number of Steps per Day Among Adults With Cardiometabolic Conditions: Meta-analysis of Individual Patient Data From Randomized Controlled Trials.

BACKGROUND: Current evidence supports the use of wearable trackers by people with cardiometabolic conditions. However, as the health benefits are small and confounded by heterogeneity, there remains uncertainty as to which patient groups are most helped by wearable trackers. OBJECTIVE: This study examined the effects of wearable trackers in patients with cardiometabolic conditions to identify subgroups of patients who most benefited and to understand interventional differences. METHODS: We obtained individual participant data from randomized controlled trials of wearable trackers that were conducted before December 2020 and measured steps per day as the primary outcome in participants with cardiometabolic conditions including diabetes, overweight or obesity, and cardiovascular disease. We used statistical models to account for clustering of participants within trials and heterogeneity across trials to estimate mean differences with the 95% CI. RESULTS: Individual participant data were obtained from 9 of 25 eligible randomized controlled trials, which included 1481 of 3178 (47%) total participants. The wearable trackers revealed that over the median duration of 12 weeks, steps per day increased by 1656 (95% CI 918-2395), a significant change. Greater increases in steps per day from interventions using wearable trackers were observed in men (interaction coefficient -668, 95% CI -1157 to -180), patients in age categories over 50 years (50-59 years: interaction coefficient 1175, 95% CI 377-1973; 60-69 years: interaction coefficient 981, 95% CI 222-1740; 70-90 years: interaction coefficient 1060, 95% CI 200-1920), White patients (interaction coefficient 995, 95% CI 360-1631), and patients with fewer comorbidities (interaction coefficient -517, 95% CI -1188 to -11) compared to women, those aged below 50, non-White patients, and patients with multimorbidity. In terms of interventional differences, only face-to-face delivery of the tracker impacted the effectiveness of the interventions by increasing steps per day. CONCLUSIONS: In patients with cardiometabolic conditions, interventions using wearable trackers to improve steps per day mostly benefited older White men without multimorbidity. TRIAL REGISTRATION: PROSPERO CRD42019143012; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=143012.

Alcohol Exerts a Shifted U-Shaped Effect on Central Blood Pressure in Young Adults.

BACKGROUND: Consumption of 1-2 alcoholic beverages daily has been associated with a lower risk of cardiovascular disease and all-cause mortality in middle-aged and older adults. Central blood pressure has emerged as a better predictor of cardiovascular risk than peripheral blood pressure. However, the effects of habitual alcohol consumption on central blood pressure particularly in young adults, who are among the largest consumers of alcohol in North America, have yet to be investigated. OBJECTIVE: We aimed to study the effect of alcohol consumption on central and peripheral blood pressure, and arterial stiffness in young adults. DESIGN: Cross-sectional observational study. MAIN MEASURES: Using a standardized questionnaire, alcohol consumption (drinks/week) was queried; participants were classified as non- (< 2), light (2-6), moderate (women 7-9, men 7-14), and heavy drinkers (women > 9, men > 14). Central blood pressure and arterial stiffness were measured using applanation tonometry. KEY RESULTS: We recruited 153 healthy, non-smoking, non-obese individuals. We found a U-shaped effect of alcohol consumption on blood pressure. Light drinkers had significantly lower central systolic and mean arterial blood pressure, but not peripheral blood pressure when compared to non- and moderate/heavy drinkers (P < 0.05). No significant associations with arterial stiffness parameters were noted. CONCLUSIONS: A U-shaped relationship was found between alcohol consumption and central and mean arterial blood pressure in young individuals, which importantly, was shifted towards lower levels of alcohol consumption than currently suggested. This is the first study, to our knowledge, that examines the effect of alcohol consumption on central blood pressure and arterial stiffness exclusively in young individuals. Prospective studies are needed to confirm the relationships observed herein.

Methodological considerations for the measurement of arterial stiffness using applanation tonometry.

INTRODUCTION: Accurate comparisons of carotid--femoral pulse wave velocity (cfPWV) within and across studies require standardized procedures. Guidelines suggest reporting the average of at least two cfPWV measurements; if the difference exceeds 0.5 m/s, a third measurement should be taken, and the median reported. Another method involves repeating measurements until two values are within 0.5 m/s. However, in many studies, duplicate measurements are averaged irrespective of the difference between readings. We evaluated the impact of these methods on the reported cfPWV value. METHODS: Measurements of cfPWV (SphygmoCor) from five studies included individuals spanning a wide age range, with or without comorbid conditions, and pregnant women. In participants with at least three high-quality measurements, differences between the median value (MED) and the average of the first two cfPWV measurements (AVG1) and the average of two cfPWV measurements within 0.5 m/s (AVG2) were evaluated using paired t-tests and Bland--Altman plots. RESULTS: Participants' mean age was 50 ±â€Š14 years and BMI was 28.0 ±â€Š5.5 kg/m2 (N = 306, 79% women). The overall mean difference was -0.10 m/s (95% CI 0.17 to -0.04) between MED and AVG1, and 0.11 m/s (95% CI 0.05--0.17) between MED and AVG2. The absolute difference exceeded 0.5 m/s in 34% (MED-AVG1) and 22% (MED-AVG2) of participants, and 1 m/s in 8% of participants (both MED-AVG1 and MED-AVG2). Scatter around the bias line increased with higher mean cfPWV values. CONCLUSION: Although the overall mean difference in cfPWV between protocols was not clinically relevant, large variation led to absolute differences exceeding 0.5 m/s in a large proportion of participants.

A trajectory analysis of daily step counts during a physician-delivered intervention.

OBJECTIVES: Higher steps are associated with lower mortality and cardiovascular event rates. We previously demonstrated that tailored physician-delivered step count prescriptions successfully increased steps/day in adults with type 2 diabetes mellitus (T2DM) and/or hypertension. In the present analysis, we examined patterns of step count change and the factors that influence different responses. DESIGN: Longitudinal observational study METHODS: Active arm participants (n=118) recorded steps/day. They received a step count prescription from their physician every 3-4 months. We computed mean steps/day and changes from baseline for sequential 30-day periods. Group-based trajectory modeling was applied. RESULTS: Four distinct trajectories of mean steps/day emerged, distinguishable by differences in baseline steps/day: sedentary (19%), low active (40%), somewhat active (30%) and active (11%). All four demonstrated similar upward slopes. Three patterns emerged for the change in steps from baseline: gradual decrease (30%), gradual increase with late decline (56%), and rapid increase with midpoint decline (14%); thus 70% had an increase from baseline. T2DM (odd ratios [OR]: 3.7, 95% CI 1.7, 7.7) and age (OR per 10-year increment: 2, 95% CI 1.3, 2.8) were both associated with starting at a lower baseline but participants from these groups were no less likely than others to increase steps/day. CONCLUSIONS: T2DM and older age were associated with lower baseline values but were not indicators of likelihood of step count increases. A physician-delivered step count prescription and monitoring strategy has strong potential to be effective in increasing steps irrespective of baseline counts and other clinical and demographic characteristics.

Adults With Type 2 Diabetes Mellitus Exhibit a Greater Exercise-Induced Increase in Arterial Stiffness and Vessel Hemodynamics.

Individuals with type 2 diabetes mellitus (T2DM) have a greater blood pressure (BP) response to acute maximal exercise compared to those without T2DM; however, whether they exhibit a different arterial stiffness response to maximal exercise has yet to be explored. Adults with (n=66) and without T2DM (n=61) underwent an arterial stress test: at rest and immediately postexercise, carotid-femoral pulse wave velocity, the gold standard measure of arterial stiffness, brachial BP, heart rate, and other hemodynamic measurements were assessed. Linear regression models were used to evaluate between-group differences at rest, and the response to exercise (postexercise value), adjusting for covariates including BP and heart rate when relevant, and the corresponding baseline value of each parameter. All participants (mean±SD: age 59.3±10.6 years; body mass index 31.2±3.9 kg/m2) had hypertension (mean BP 130±14/80±9 mm Hg). At rest, participants with T2DM had significantly higher carotid-femoral pulse wave velocity (10.3±2.7 versus 9.1±1.9 m/s), heart rate (69±11 versus 66±10 beats/min), and lower diastolic BP (79±9 versus 83±9 mm Hg), but systolic BP (129±15 versus 131±13 mm Hg) was similar. In response to exercise, participants with T2DM showed greater increases in carotid-femoral pulse wave velocity (1.6 [95% CI, 0.4-2.9 m/s]) and systolic BP (9 [95% CI, 1-17 mm Hg]) than participants without T2DM. A greater proportion of participants with T2DM had a hypertensive response to exercise compared to participants without T2DM (n=23, 35% versus n=11, 18%; P=0.033). By incorporating exercise as a vascular stressor, we provide evidence of a greater increase in arterial stiffness in individuals with T2DM, independently of resting arterial stiffness, and the BP postexercise.

A qualitative evaluation of a physician-delivered pedometer-based step count prescription strategy with insight from participants and treating physicians.

AIMS: The integration of pedometers into clinical practice has the potential to enhance physical activity levels in patients with chronic disease. Our SMARTER randomized controlled trial demonstrated that a physician-delivered step count prescription strategy has measurable effects on daily steps, glycemic control, and insulin resistance in patients with type 2 diabetes and/or hypertension. In this study, we aimed to understand perceived barriers and facilitators influencing successful uptake and sustainability of the strategy, from patient and physician perspectives. METHODS: Qualitative in-depth interviews were conducted in a purposive sample of physicians (n = 10) and participants (n = 20), including successful and less successful cases in terms of pedometer-assessed step count improvements. Themes that achieved saturation in either group through thematic analysis are presented. RESULTS: All participants appreciated the pedometer-based monitoring combined with step count prescriptions. Accountability to physicians and support offered by the trial coordinator influenced participant motivation. Those who increased step counts adopted strategies to integrate more steps into their routines and were able to overcome weather-related barriers by finding indoor alternative options to outdoor steps. Those who decreased step counts reported difficulty in overcoming weather-related challenges, health limitations and work constraints. Physicians indicated the strategy provided a framework for discussing physical activity and motivating patients, but emphasized the need for support from allied professionals to help deliver the strategy in busy clinical settings. CONCLUSION: A physician-delivered step count prescription strategy was feasibly integrated into clinical practice and successful in engaging most patients; however, continual support is needed for maximal engagement and sustained use.

The impact of accelerometer wear location on the relationship between step counts and arterial stiffness in adults treated for hypertension and diabetes.

OBJECTIVES: Accelerometer placement at the wrist is convenient and increasingly adopted despite less accurate physical activity (PA) measurement than with waist placement. Capitalizing on a study that started with wrist placement and shifted to waist placement, we compared associations between PA measures derived from different accelerometer locations with a responsive arterial health indicator, carotid-femoral pulse wave velocity (cfPWV). DESIGN: Cross-sectional study. METHODS: We previously demonstrated an inverse association between waist-worn pedometer-assessed step counts (Yamax SW-200, 7 days) and cfPWV (-0.20m/s, 95% CI -0.28, -0.12 per 1000 step/day increment) in 366 adults. Participants concurrently wore accelerometers (ActiGraph GT3X+), most at the waist but the first 46 at the wrist. We matched this subgroup with participants from the 'waist accelerometer' group (sex, age, and pedometer-assessed steps/day) and assessed associations with cfPWV (applanation tonometry, Sphygmocor) separately in each subgroup through linear regression models. RESULTS: Compared to the waist group, wrist group participants had higher step counts (mean difference 3980 steps/day; 95% CI 2517, 5443), energy expenditure (967kcal/day, 95% CI 755, 1179), and moderate-to-vigorous-PA (138min; 95% CI 114, 162). Accelerometer-assessed step counts (waist) suggested an association with cfPWV (-0.28m/s, 95% CI -0.58, 0.01); but no relationship was apparent with wrist-assessed steps (0.02m/s, 95% CI -0.24, 0.27). CONCLUSIONS: Waist but not wrist ActiGraph PA measures signal associations between PA and cfPWV. We urge researchers to consider the importance of wear location choice on relationships with health indicators.

The Impact of Intradialytic Pedaling Exercise on Arterial Stiffness: A Pilot Randomized Controlled Trial in a Hemodialysis Population.

OBJECTIVES: Regular exercise is known to reduce arterial stiffness (AS) in hemodialysis patients. However, the impact of a more realistic intradialytic form of exercise, such as pedaling, is unclear. We aimed to examine (i) the effect of intradialytic pedaling exercise on AS over 4 months and (ii) the longer term effect of pedaling on AS 4 months after exercise cessation. METHODS: Patients on stable in-center hemodialysis (3 x/week) were randomly assigned 1:1 to either intradialytic pedaling exercise (EX) or to a control group receiving usual hemodialysis (nonEX) for 4 months. At baseline and 4 months, peripheral and central blood pressure (BP) indices, heart rate (HR), augmentation index HR corrected (AIx75), and carotid-femoral pulse wave velocity (cfPWV) were assessed (applanation tonometry). Measurements were repeated in the EX group 4 months postexercise cessation. RESULTS: As per protocol analysis was completed in 10 EX group participants (58 ± 17 years, body mass index 26 ± 4 kg/m2) and 10 nonEX group participants (53 ± 15 years, body mass index 27 ± 6 kg/m2). Peripheral and central BP was unchanged in both groups. AIx75 was unchanged in the EX group, however, a significant median increase of 3.5% [interquartile range, IQR 1.0, 8.5] was noted in the nonEX group (P = 0.009). We noted a significantly greater absolute decrease in cfPWV in the EX group compared to controls: -1.00 [IQR -1.95, 0.05] vs. 0.20 [IQR -0.10, 0.90] (P = 0.033). Interestingly, the decrease in cfPWV observed in the EX group was partially reversed 4 months after exercise cessation. CONCLUSION: Intradialytic pedaling exercise has a beneficial impact on AS. This relationship warrants further investigation. CLINICAL TRIALS REGISTRATION: Trial Number #NCT03027778 (clinicaltrials.gov).

Physician step prescription and monitoring to improve ARTERial health (SMARTER): A randomized controlled trial in patients with type 2 diabetes and hypertension.

AIMS: There are few proven strategies to enhance physical activity and cardiometabolic profiles in patients with type 2 diabetes and hypertension. We examined the effects of physician-delivered step count prescriptions and monitoring. METHODS: Participants randomized to the active arm were provided with pedometers and they recorded step counts. Over a 1-year period, their physicians reviewed their records and provided a written step count prescription at each clinic visit. The overall goal was a 3000 steps/day increase over 1 year (individualized rate of increase). Control arm participants were advised to engage in physical activity 30 to 60 min/day. We evaluated effects on step counts, carotid femoral pulse wave velocity (cfPWV, primary) and other cardiometabolic indicators including haemoglobin A1c in diabetes (henceforth abbreviated as A1c) and Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) in participants not receiving insulin therapy. RESULTS: A total of 79% completed final evaluations (275/347; mean age, 60 years; SD, 11). Over 66% of participants had type 2 diabetes and over 90% had hypertension. There was a net 20% increase in steps/day in active vs control arm participants (1190; 95% CI, 550-1840). Changes in cfPWV were inconclusive; active vs control arm participants with type 2 diabetes experienced a decrease in A1c (-0.38%; 95% CI, -0.69 to -0.06). HOMA-IR also declined in the active arm vs the control arm (ie, assessed in all participants not treated with insulin; -0.96; 95% CI, -1.72 to -0.21). CONCLUSIONS: A simple physician-delivered step count prescription strategy incorporated into routine clinical practice led to a net 20% increase in step counts; however, this was below the 3000 steps/day targeted increment. While conclusive effects on cfPWV were not observed, there were improvements in both A1c and insulin sensitivity. Future studies will evaluate an amplified intervention to increase impact.

A systematic review on the effect of acute aerobic exercise on arterial stiffness reveals a differential response in the upper and lower arterial segments.

The objective of this systematic review was to provide insight into the controversy that still abounds as to the impact of acute aerobic exercise on immediate changes in arterial stiffness. Electronic databases were searched to identify articles assessing the effects of acute aerobic exercise on parameters of arterial stiffness. Eligible studies included arterial stiffness measurements before and after acute aerobic exercise in healthy human subjects. Forty-three studies were included. The effect of acute aerobic exercise on arterial stiffness was found to be dependent on the anatomical segment assessed, and on the timing of the measurement post-exercise. Arterial stiffness of the central and upper body peripheral arterial segments was found to be increased relative to resting values immediately post-exercise (0-5 min), whereas, thereafter (>5 min), decreased to a level at or below resting values. In the lower limbs, proximal to the primary working muscles, arterial stiffness decreased immediately post-exercise (0-5 min), which persisted into the recovery period post-exercise (>5 min). This systematic review reveals a differential response to acute exercise in the lower and upper/central arterial segments in healthy adult subjects. We further showed that the effect of acute aerobic exercise on arterial stiffness is dependent on the timing of the measurements post-exercise. Therefore, when assessing the overall impact of exercise on arterial stiffness, it is important to consider the arterial segment being analyzed and measurement time point, as failure to contextualize the measurement can lead to conflicting results and misleading clinical inferences.

From rest to stressed: endothelin-1 levels in young healthy smokers and non-smokers.

INTRODUCTION: Endothelin-1 (ET-1) is a potent vasoconstrictor produced by vascular endothelial cells, and a known marker of endothelial dysfunction. However, the acute and chronic effects of smoking and nicotine gum on the ET-1 response to acute physical stress in young healthy smokers have not been investigated. METHODS: Healthy smokers (n=35) and non-smokers (n=35) underwent an exercise test to exhaustion (maximal oxygen consumption) on a treadmill. Smokers were assessed a) after 12h smoking abstinence (termed chronic smoking), b) immediately after smoking one cigarette (termed acute smoking), and c) immediately after chewing nicotine gum. Blood was drawn immediately pre-exercise, and 3 minutes post-exercise. During exercise, cardiorespiratory parameters were obtained breath-by-breath using an automated metabolic cart. Plasma ET-1 levels were quantified using enzyme-linked immunosorbent-assay. The above protocol was designed to incorporate exercise as a vascular stressor to reveal changes that would not be detected at rest. RESULTS: Mean age was 28.6±7.2 years and body mass index (BMI) was 23.6±3.2 kg/m(2). Post-exercise ET-1 levels were significantly lower than pre-exercise levels in non-smokers (P<0.001) and smokers under all three conditions (P=0.005, P<0.001, P=0.001, respectively). There were no differences in post-exercise ET-1 levels between non-smokers and smokers under all three conditions, however the absolute and relative decrease in ET-1 levels was significantly smaller in chronic smokers compared with non-smokers (P=0.007 and P=0.004). Chronic smokers had a significantly lower exercise-induced change in tidal volume (P=0.050), fraction of expired CO2 (P=0.021), oxygen consumption (P=0.005), carbon dioxide elimination (P=0.004) and peak expiratory flow (P=0.003) compared with non-smokers. Furthermore, the decrease in ET-1 observed in non-smokers in response to exercise was significantly associated with exercise induced-changes in inspiratory time, time for a tidal volume cycle, respiratory frequency, inspired minute ventilation and peak inspiratory flow. CONCLUSIONS: An acute decrease of circulating ET-1 in response to acute maximal exercise in young healthy individuals was noted. Chronic smokers had a significantly diminished decrease in ET-1 compared with non-smokers, however there were no significant differences in the ET-1 response between smokers under the three smoking conditions. Smokers were not able to achieve the same exercise-induced changes in cardiorespiratory parameters as non-smokers. By incorporating exercise as a vascular stressor in our study, we have taken a novel approach to provide evidence of an altered ET-1 and cardiorespiratory response that would not otherwise be observed at rest in young active healthy smokers.

Plasma irisin levels progressively increase in response to increasing exercise workloads in young, healthy, active subjects.

BACKGROUND: Irisin, a recently discovered myokine, has been shown to induce browning of white adipose tissue, enhancing energy expenditure and mediating some of the beneficial effects of exercise. We aimed to estimate the time frame of changes in irisin levels after acute exercise and the effect of different exercise workloads and intensities on circulating irisin levels immediately post-exercise. METHODS: In a pilot study, four healthy subjects (22.5±1.7 years) underwent maximal workload exercise (maximal oxygen consumption, VO2 max) and blood was drawn at prespecified intervals to define the time frame of pre- and post-exercise irisin changes over a 24-h period. In the main study, 35 healthy, non-smoking (23.0±3.3 years) men and women (n=20/15) underwent three exercise protocols ≥48-h apart, in random order: i) maximal workload (VO2 max); ii) relative workload (70% of VO2 max/10 min); and iii) absolute workload (75 W/10 min). Blood was drawn immediately pre-exercise and 3 min post-exercise. RESULTS: In the pilot study, irisin levels increased by 35% 3 min post-exercise, then dropped and remained relatively constant. In the main study, irisin levels post-exercise were significantly higher than those of pre-exercise after all workloads (all, P<0.001). Post-to-pre-exercise differences in irisin levels were significantly different between workloads (P=0.001), with the greatest increase by 34% following maximal workload (P=0.004 vs relative and absolute). CONCLUSIONS: Circulating irisin levels were acutely elevated in response to exercise, with a greater increase after maximal workload. These findings suggest that irisin release could be a function of muscle energy demand. Future studies need to determine the underlying mechanisms of irisin release and explore irisin's therapeutic potential.