Endothelial Damage Arising From High Salt Hypertension Is Elucidated by Vascular Bed Systematic Profiling.

BACKGROUND: Considerable evidence links dietary salt intake with the development of hypertension, left ventricular hypertrophy, and increased risk of stroke and coronary heart disease. Despite extensive epidemiological and basic science interrogation of the relationship between high salt (HS) intake and blood pressure, it remains unclear how HS impacts endothelial cell (EC) and vascular structure in vivo. This study aims to elucidate HS-induced vascular pathology using a differential systemic decellularization in vivo approach. METHODS: We performed systematic molecular characterization of the endothelial glycocalyx and EC proteomes in mice with HS (8%) diet-induced hypertension versus healthy control animals. Isolation of eGC and EC compartments was achieved using differential systemic decellularization in vivo methodology. Altered protein expression in hypertensive compared to normal mice was characterized by liquid chromatography tandem mass spectrometry. Proteomic results were validated using functional assays, microscopic imaging, and histopathologic evaluation. RESULTS: Proteomic analysis revealed a significant downregulation of eGC and associated proteins in HS diet-induced hypertensive mice (among 1696 proteins identified in this group, 723 were markedly decreased in abundance, while only 168 were increased in abundance. Bioinformatic analysis indicated substantial derangement of the eGC layer, which was subsequently confirmed by fluorescent and electron microscopy assessment of vessel damage ex vivo. In the EC fraction, HS-induced hypertension significantly altered protein mediators of contractility, metabolism, mechanotransduction, renal function, and the coagulation cascade. In particular, we observed dysregulation of integrin subunits α2, α2b, and α5, which was associated with arterial wall inflammation and substantial infiltration of CD68+ monocyte-macrophages. Consequently, HS-induced hypertensive mice also displayed reduced vascular integrity of multiple organs including lungs, kidneys, and heart. CONCLUSIONS: These findings provide novel molecular insight into HS-induced structural changes in eGC and EC composition that may increase cardiovascular risk and potentially guide the development of new diagnostics and therapeutic interventions.

Childhood household dysfunction is associated with reduced left ventricular mass in young adulthood.

The effect of adverse childhood experiences (ACEs) on left ventricular mass (LVM) and left ventricular function remains largely unknown across the lifespan. This study investigated the influence of ACEs on LVM and left ventricular function and whether inflammation influences this relationship. Two hundred forty-eight healthy young adults participated and a final sample of 217 (age, 22.6 ± 0.1 yr; females, 114) had complete data. Echocardiographic assessment of LVM was indexed to height2.7 (LVMHT) and body surface area (LVMBSA). Ejection fraction (EF) and fractional shortening were also assessed. Interleukin-6 (IL-6), C-reactive protein, tumor necrosis factor-α, and matrix metalloproteinase (MMP) 1-3 were measured and ACEs exposures were assessed based on exposure and nonexposure to childhood household dysfunction and maltreatment, and quantity of adversity, (i.e., <4 ACEs and ≥4 ACEs). Individuals who experienced household dysfunction demonstrated lower LVM, LVMHT, and LVMBSA (P < 0.01) and greater IL-6 (P < 0.05) than those who did not experience household dysfunction. Reduced MMP3 was present in individuals who experienced maltreatment (P < 0.05) and ≥4 ACEs (P < 0.01) compared with no maltreatment and <4 ACEs, respectively. After controlling for covariates (i.e., sex, recent life stress, height, body mass index, smoking, physical activity, and inflammation), a significant negative effect of household dysfunction on LVM, LVMHT, and LVMBSA persisted. Likewise, a negative effect on EF independent of covariates was observed in individuals who experienced ≥4 ACEs. As such, alterations in LVM and EF may be perpetuated through a toxic home environment, promoting left ventricular underdevelopment in young adulthood. The effect of which in midlife and beyond requires additional investigation.NEW & NOTEWORTHY This is the first study to investigate the influence of adverse childhood experiences (ACEs) on left ventricular mass (LVM) and function. We identified experiencing any childhood household dysfunction was associated with lower LVM in young adults independent of sex, recent life stress, BMI and height, smoking, physical activity, and inflammation. We speculate an inflection point in LVM occurs in midlife predisposing these individuals toward a hypertrophic profile and elevated risk of heart disease in later life, although this requires longitudinal investigation.

Adverse childhood experiences are associated with altered cardiovascular reactivity to head-up tilt in young adults.

Adverse childhood experiences (ACEs) are associated with greater prevalence of cardiovascular disease and altered acute stress reactivity. The current study investigated the effect of ACEs on hemodynamic and autonomic responses to orthostatic stress imposed by 60° head-up tilt (HUT) in young adults. Two-hundred twenty-six healthy young adults (age = 22.6 ± 1.5 yr; n = 116 females) without cardiovascular disease participated and had complete data. Participants underwent supine blood pressure (BP), R-R interval (RRI), cardiac output (CO), total peripheral resistance (TPR), and cardiovagal baroreflex sensitivity (cvBRS) testing followed by a transition to 60° HUT where measures were reassessed. Childhood adversity exposures were assessed based on categorical exposure and nonexposure to childhood household dysfunction and maltreatment, and <4 and ≥4 types of ACEs. Significantly greater increases in SBP (P < 0.05), DBP, MAP, and TPR (P < 0.01; all) following 60° HUT were observed in individuals with ≥4 compared with those with <4 types of ACEs. Attenuated decreases in RRI and cvBRS were observed in those with ≥4 types of ACEs (P < 0.05). Experiencing ≥4 types of ACEs was associated with augmented BP and TPR reactivity and a blunted decrease in cvBRS in response to 60° HUT in young adults. Results suggest that a reduced vagal response to orthostatic stress is present in those who have experienced ≥4 types of ACEs that may promote autonomic dysfunction. Future research examining the sympathetic and vagal baroreflex branches is warranted.

Skin Blood Flow Responses to Acetylcholine, Local Heating, and to 60% VO2max exercise with and without Nitric Oxide inhibition, in Boys vs. Girls.

PURPOSE: To determine sex-related differences in the skin blood flow (SkBF) response to exercise, local heating, and acetylcholine (ACh) in children, and to assess nitric oxide contribution to the SkBF response. METHODS: Forearm SkBF during local heating (44°C), ACh iontophoresis, and exercise (30-min cycling and 60% of maximum oxygen consumption) was assessed, using laser Doppler fluxmetry, in 12 boys and 12 girls (7-13 y old), with and without nitric oxide synthase inhibition, using Nω-nitro-L-arginine methyl ester iontophoresis. RESULTS: Local-heating-induced and ACh-induced SkBF increase were not different between boys and girls (local heating: 1445% [900%] and 1432% [582%] of baseline, P = .57; ACh: 673% [434%] and 558% [405%] of baseline, respectively, P = .18). Exercise-induced increase in SkBF was greater in boys than girls (528% [290%] and 374% [192%] of baseline, respectively, P = .03). Nω-nitro-L-arginine methyl ester blunted the SkBF response to ACh and during exercise (P < .001), with no difference between sexes. CONCLUSION: SkBF responses to ACh and local heat stimuli were similar in boys and girls, while the increase in SkBF during exercise was greater in boys. The apparent role of nitric oxide was not different between boys and girls. It is suggested that the greater SkBF response in boys during exercise was related to greater relative heat production and dissipation needs at this exercise intensity. The response to body size-related workload should be further examined.

Linking the hemodynamic consequences of adverse childhood experiences to an altered HPA axis and acute stress response.

Adverse childhood experiences (ACEs), such as maltreatment and severe household dysfunction, represent a significant threat to public health as ACEs are associated with increased prevalence of several chronic diseases. Biological embedding, believed to be rooted in dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, is the prevailing theory by which chronic diseases become imprinted in individuals following childhood adversity. A shift towards HPA axis hypoactivity occurs in response to ACEs exposure and is proposed to contribute towards altered cortisol secretion, chronic low-grade inflammation, and dysregulated hemodynamic and autonomic function. This shift in HPA axis activity may be a long-term effect of glucocorticoid receptor methylation with downstream effects on hemodynamic and autonomic function. Emerging evidence suggests syncopal tendencies are increased among those with ACEs and coincides with altered neuroimmune function. Similarly, chronic low-grade inflammation may contribute towards arterial baroreceptor desensitization through increased arterial stiffness, negatively impacting autonomic regulation following posture change and increasing rates of syncope in later life, as has been previously highlighted in the literature. Although speculative, baroreceptor desensitization may be secondary to increased arterial stiffness and changes in expression of glucocorticoid receptors and arginine vasopressin, which are chronically altered by ACEs. Several research gaps and opportunities exist in this field and represent prospective areas for future investigation. Here, we synthesize current findings in the areas of acute psychosocial stress reactivity pertaining to HPA axis function, inflammation, and hemodynamic function while suggesting ideas for future research emphasizing systemic interactions and postural stress assessments among those with ACEs. This review aims to identify specific pathways which may contribute towards orthostatic intolerance in populations with history of childhood adversity.

Cytokine concentrations in saliva vs. plasma at rest and in response to intense exercise in adolescent athletes.

BACKGROUND: Salivary measures are advantageous in conducting large paediatric studies involving repeated measures. However, research measuring salivary cytokines in youth is limited. AIM: Compare salivary with plasma concentrations of inflammatory cytokines at rest and following exercise in adolescent swimmers (21 male, 22 female). METHODS: Following collection of resting saliva and blood samples, participants performed a bout of high-intensity interval swimming, with samples taken again ∼15 min post-swimming and analysed for interleukin-6 (IL-6), interleukin 10 (IL-10), and tumour necrosis factor-alpha (TNF-α). RESULTS: Resting IL-10 was significantly lower, while IL-6 and TNF-α were significantly higher in saliva compared with plasma. IL-10 increased from pre- to post-swimming in plasma, but less so in saliva (51% vs. 29%; p = 0.02). TNF-α decreased post-swimming in saliva, but not in plasma (-27% vs -1%; p = 0.01). IL-6 decreased post-swimming in saliva compared with plasma (-21% vs. -3%; p = 0.06). Intraclass correlation coefficients (ICC) revealed no association between salivary and plasma IL-6 and TNF-α, while IL-10 showed a weak correlation only at rest (ICC = 0.39; p = 0.05). CONCLUSIONS: Differences in concentrations and exercise responses, along with weak correlations, suggest that salivary cytokine levels are not an accurate representation of blood cytokine levels, and should not be used as a surrogate measure in paediatric studies.

Cardiac parasympathetic activity and ventricular diastolic interactions in individuals with spinal cord injury.

STUDY DESIGN: Cohort cross-sectional study. OBJECTIVE: To investigate the relationship between cardiac vagal activity and left ventricular filling at rest and during vagal stimulation, via the cold face test (CFT), in individuals with spinal cord injury (SCI). SETTING: University-based laboratory at Brock University, St. Catharines, ON, Canada. METHODS: A total of 12 able-bodied (age: 40 ± 8.5 years) and 13 SCI individuals (age: 41 ± 8.5 years; C4-T6; AIS: A-D) were recruited. Cardiac parasympathetic activity was assessed via heart rate variability (HRV) while LV filling was assessed by conventional echocardiography. All indices of HRV and diastolic function were obtained at rest and during cardiac vagal stimulation via the CFT. RESULTS: At baseline, the able-bodied group demonstrated strong positive correlations between HRV and early diastolic filling; however, such correlations were absent in the SCI group. The CFT resulted in elevated HRV with concomitant bradycardia in the able-bodied group, while the SCI group experienced no change in HRV or heart rate during the CFT. Able-bodied individuals showed a positive correlation between the change in HRV and the change in LV diastole during the CFT, which was attributed to increased cardiac vagal tone and not the change in heart rate, however, no relationships were observed in the SCI group. CONCLUSION: In able-bodied individuals, cardiac parasympathetic activity is associated with LV filling at rest and during elevated cardiac vagal tone. After SCI, there is a discord between vagal and LV diastolic activity, where changes in autonomic function do not influence LV filling, suggesting a disconnect between parasympathetic and cardiac function.

Corticospinal excitability is associated with hypocapnia but not changes in cerebral blood flow.

KEY POINTS: Reductions in cerebral blood flow (CBF) may be implicated in the development of neuromuscular fatigue; however, the contribution from hypocapnic-induced reductions (i.e. P ETC O2) in CBF versus reductions in CBF per se has yet to be isolated. We assessed neuromuscular function while using indomethacin to selectively reduce CBF without changes in P ETC O2 and controlled hyperventilation-induced hypocapnia to reduce both CBF and P ETC O2. Increased corticospinal excitability appears to be exclusive to reductions in P ETC O2 but not reductions in CBF, whereas sub-optimal voluntary output from the motor cortex is moderately associated with decreased CBF independent of changes in P ETC O2. These findings suggest that changes in CBF and P ETC O2 have distinct roles in modulating neuromuscular function. ABSTRACT: Although reductions in cerebral blood flow (CBF) may be involved in central fatigue, the contribution from hypocapnia-induced reductions in CBF versus reductions in CBF per se has not been isolated. This study examined whether reduced arterial PCO2 (P aC O2), independent of concomitant reductions in CBF, impairs neuromuscular function. Neuromuscular function, as indicated by motor-evoked potentials (MEPs), maximal M-wave (Mmax ) and cortical voluntary activation (cVA) of the flexor carpi radialis muscle during isometric wrist flexion, was assessed in ten males (29 ± 10 years) during three separate conditions: (1) cyclooxygenase inhibition using indomethacin (Indomethacin, 1.2 mg kg(-1) ) to selectively reduce CBF by 28.8 ± 10.3% (estimated using transcranial Doppler ultrasound) without changes in end-tidal PCO2 (P ETC O2); (2) controlled iso-oxic hyperventilation-induced reductions in P aC O2 (Hypocapnia), P ETC O2  = 30.1 ± 4.5 mmHg with related reductions in CBF (21.7 ± 6.3%); and (3) isocapnic hyperventilation (Isocapnia) to examine the potential direct influence of hyperventilation-mediated activation of respiratory control centres on CBF and changes in neuromuscular function. Change in MEP amplitude (%Mmax ) from baseline was greater in Hypocapnia tha in Isocapnia (11.7 ± 9.8%, 95% confidence interval (CI) [2.6, 20.7], P = 0.01) and Indomethacin (13.3 ± 11.3%, 95% CI [2.8, 23.7], P = 0.01) with a large Cohen's effect size (d ≥ 1.17). Although not statistically significant, cVA was reduced with a moderate effect size in Indomethacin (d = 0.7) and Hypocapnia (d = 0.9) compared to Isocapnia. In summary, increased corticospinal excitability - as reflected by larger MEP amplitude - appears to be exclusive to reduced P aC O2, but not reductions in CBF per se. Sub-optimal voluntary output from the motor cortex is moderately associated with decreased CBF, independent of reduced P aC O2.

Role of aortic arch vascular mechanics in cardiovagal baroreflex sensitivity.

Cardiovagal baroreflex sensitivity (cvBRS) measures the efficiency of the cardiovagal baroreflex to modulate heart rate in response to increases or decreases in systolic blood pressure (SBP). Given that baroreceptors are located in the walls of the carotid sinuses (CS) and aortic arch (AA), the arterial mechanics of these sites are important contributors to cvBRS. However, the relative contribution of CS and AA mechanics to cvBRS remains unclear. This study employed sex differences as a model to test the hypothesis that differences in cvBRS between groups would be explained by the vascular mechanics of the AA but not the CS. Thirty-six young, healthy, normotensive individuals (18 females; 24 ± 2 yr) were recruited. cvBRS was measured using transfer function analysis of the low-frequency region (0.04-0.15 Hz). Ultrasonography was performed at the CS and AA to obtain arterial diameters for the measurement of distensibility. Local pulse pressure (PP) was taken at the CS using a hand-held tonometer, whereas AA PP was estimated using a transfer function of brachial PP. Both cvBRS (25 ± 11 vs. 19 ± 7 ms/mmHg, P = 0.04) and AA distensibility (16.5 ± 6.0 vs. 10.5 ± 3.8 mmHg(-1) × 10(-3), P = 0.02) were greater in females than males. Sex differences in cvBRS were eliminated after controlling for AA distensibility (P = 0.19). There were no sex differences in CS distensibility (5.32 ± 2.3 vs. 4.63 ± 1.3 mmHg(-1) × 10(-3), P = 0.32). The present data demonstrate that AA mechanics are an important contributor to differences in cvBRS.

The Effects of Sex and Pubertal Maturation on Cardiovagal Baroreflex Sensitivity.

OBJECTIVE: To examine baroreflex sensitivity (BRS) across different stages of pubertal maturation in healthy children and adolescents. STUDY DESIGN: This study was cross-sectional and included 104 participants (53 males and 51 females) aged 8-18 years old. Participants were organized into 5 pubertal groups based on the criteria of Tanner; prepubertal (Tanner 1, n = 19), early-pubertal (Tanner 2, n = 16), peripubertal (Tanner 3, n = 24), late-pubertal (Tanner 4, n = 23), and postpubertal (Tanner 5 and 6, n = 22). Adiposity (fat-free mass, fat mass, and body fat%), body mass index, and demographic variables were collected. Beat-by-beat blood pressure and R-R interval were collected during supine rest to determine BRS. BRS was assessed by transfer function analysis in the low frequency range (0.05-0.15 Hz). RESULTS: The results demonstrated a sex-by-maturation interaction [F(4, 94) = 3.202, P = .019]. BRS decreased from early-to postpuberty in males (30 [7.1] vs 13.2 [7.8] ms/mm Hg), and remained unchanged in females. This led to significantly greater BRS in females compared with males, postpuberty (27 [7.3] vs 13.2 [7.8] ms/mm Hg). CONCLUSIONS: Controlling for both sex and maturation when examining BRS in children and adolescents with cardiovascular disease risk factors will aid in interpreting abnormally high or low BRS values.

Evidence of a hyperkinetic state in children with elevated blood pressure.

BACKGROUND: Left ventricular hypertrophy (LVH) and elevated left ventricular mass index (LVMI) are important predictors of cardiovascular morbidity and mortality in adults. Children with hypertension and pre-hypertension demonstrate LVH and greater LVMI compared to normotensive children. The impact of blood pressure (BP) on early changes in left ventricular properties provides an opportunity to understand and identify cardiovascular risk early in childhood. AIM: The aim of this study was to assess left ventricular structural and functional properties in a sample of children across a wide range of BP values. SUBJECTS AND METHODS: Children aged 11-14-years were divided into BP groups: hypertensives (HTN; ≥95th percentile; n = 21) and normotensives (NTN; <90th percentile; n = 85) based on BP measures taken at two time points. Resting supine heart rate (HR), cardiac output (CO) and total peripheral resistance (TPR) were collected along with left ventricular structural and functional properties using ultrasound sonography. RESULTS: LVMI and TPR were not different between groups. CO, HR and left ventricular end-diastolic and end-systolic volumes were elevated in the HTN group. Furthermore, HR and body mass index were found to be independent predictors of BP group status in children. CONCLUSION: These findings show that children with elevated BP are characterized by high HR and CO and normal TPR. Also, the results identify HR as a predictor of BP group status in early childhood.

Correction: Liu et al. Weight Change and Risk of Atherosclerosis Measured by Carotid Intima-Media Thickness (cIMT) from a Prospective Cohort-Analysis of the First-Wave Follow-Up Data of the Canadian Longitudinal Study on Aging (CLSA). J. Cardiovasc. Dev. Dis. 2023, 10, 435.

There was missing information in the back matter of the original publication [...].

Examining the Light Heart Mobile Device App for Assessing Human Pulse Interval and Heart Rate Variability: Validation Study.

BACKGROUND: Pulse interval is a biomarker of psychological and physiological health. Pulse interval can now be assessed using mobile phone apps, which expands researchers' ability to assess pulse interval in the real world. Prior to implementation, measurement accuracy should be established. OBJECTIVE: This investigation evaluated the validity of the Light Heart mobile app to measure pulse interval and pulse rate variability in healthy young adults. METHODS: Validity was assessed by comparing the pulse interval and SD of normal pulse intervals obtained by Light Heart to the gold standard, electrocardiogram (ECG), in 14 young healthy individuals (mean age 24, SD 5 years; n=9, 64% female) in a seated posture. RESULTS: Mean pulse interval (Light Heart: 859, SD 113 ms; ECG: 857, SD 112 ms) demonstrated a strong positive linear correlation (r=0.99; P<.001) and strong agreement (intraclass correlation coefficient=1.00, 95% CI 0.99-1.00) between techniques. The Bland-Altman plot demonstrated good agreement for the mean pulse interval measured with Light Heart and ECG with evidence of fixed bias (-1.56, SD 1.86; 95% CI -5.2 to 2.1 ms), suggesting that Light Heart overestimates pulse interval by a small margin. When Bland-Altman plots were constructed for each participant's beat-by-beat pulse interval data, all participants demonstrated strong agreement between Light Heart and ECG with no evidence of fixed bias between measures. Heart rate variability, assessed by SD of normal pulse intervals, demonstrated strong agreement between techniques (Light Heart: mean 73, SD 23 ms; ECG: mean 73, SD 22 ms; r=0.99; P<.001; intraclass correlation coefficient=0.99, 95% CI 0.97-1.00). CONCLUSIONS: This study provides evidence to suggest that the Light Heart mobile app provides valid measures of pulse interval and heart rate variability in healthy young adults.

Adverse childhood experiences and the cardiovascular health of children: a cross-sectional study.

BACKGROUND: Adverse childhood experiences (ACEs), such as abuse, household dysfunction, and neglect, have been shown to increase adults' risk of developing chronic conditions and risk factors for chronic conditions, including cardiovascular disease (CVD). Much less work has investigated the effect of ACEs on children's physical health status that may lead to adult chronic health conditions. Therefore, the present study examined the relationship between ACEs and early childhood risk factors for adult cardiovascular disease. METHODS: 1 234 grade six to eight students participated in school-based data collection, which included resting measures of blood pressure (BP), heart rate (HR), body mass index (BMI) and waist circumference (WC). Parents of these children completed an inventory of ACEs taken from the Childhood Trust Events Survey. Linear regression models were used to assess the relationship between experiencing more than 4 ACEs experienced, systolic BP, HR, BMI and WC. In additional analysis, ACEs were assessed ordinally in their relationship with systolic BP, HR, and BMI as well as clinical obesity and hypertension status. RESULTS: After adjustment for family education, income, age, sex, physical activity, and parental history of hypertension, and WC for HR models, four or more ACEs had a significant effect on HR (b = 1.8 bpm, 95% CI (0.1-3.6)) BMI (b =1.1 kg/m2, 95% CI (0.5-1.8)), and WC (b = 3.6 cm, 95% CI (1.8-5.3)). A dose-response relationship between ACE accumulation and both BMI and WC was also found to be significant. Furthermore, accumulation of 4 or more ACEs was significantly associated with clinical obesity (95th percentile), after controlling for the aforementioned covariates. CONCLUSIONS: In a community sample of grade six to eight children, accumulation of 4 or more ACEs significantly increased BMI, WC and resting HR. Therefore, risk factors related to reported associations between ACEs and cardiovascular outcomes among adults are identifiable in childhood suggesting earlier interventions to reduce CVD risk are required.

The effect of adiposity on the relationship between indicators of maturity in peri-pubertal children.

BACKGROUND: Although the relation between body fatness and maturation has been the subject of much research, somatic maturity as assessed by sex-specific regression equations, has yet to be investigated in a population of overweight and obese children. AIM: To examine whether adiposity affects the relationship between somatic and skeletal maturity in peri-pubertal children and if increased adiposity is related to earlier maturation. SUBJECTS AND METHODS: A total of 172 girls and boys (12.8 ± 0.9 years of age) participated in the study. Participants were categorized as normal weight (NW, < 85(th) percentile) or overweight/obese (OW/OB, ≥ 85(th) percentile) based on body mass index and matched for chronological and skeletal age. Skeletal age was assessed across the radial and ulnar epiphyses using quantitative ultrasound. Somatic maturity was assessed as years from age of peak height velocity (aPHV), estimated using prediction equations. Peripheral adiposity was determined by the sum of two skin-folds. RESULTS: Years from aPHV was significantly higher (p < 0.001) in OW/OB girls, but not in OW/OB boys. Skeletal age was associated with years from aPHV in NW and OW/OB boys (r = 0.87 vs 0.86, p < 0.001) and girls (r = 0.83 vs 0.72, p < 0.001). Among peri-pubertal youth of similar chronological and skeletal age, OW/OB girls were more somatically mature than their NW peers. CONCLUSION: It is concluded that excess peripheral adiposity in girls may affect the estimated somatic maturity, as reflected in years from aPHV.

Weight Change and Risk of Atherosclerosis Measured by Carotid Intima-Media Thickness (cIMT) from a Prospective Cohort-Analysis of the First-Wave Follow-Up Data of the Canadian Longitudinal Study on Aging (CLSA).

To explore impact of weight change (WC) on risk of atherosclerosis measured by cIMT, 20,700 participants from the CLSA follow-up were included in analysis. WC was defined as the difference of weight measured at follow-up and baseline, then quartered into four groups (Q1-Q4). cIMT > 1.0 mm was defined as high risk for atherosclerosis. Adjusted odds ratio (OR (95% CI)) from logistic regression models were used to evaluate the association between WC and risk of atherosclerosis. At follow-up, participants had gained 0.118 kg weight, on average, and 16.4% of them were at high risk for atherosclerosis. The mean levels of cIMT were comparable between participants from Q1 to Q4. Compared to Q2 (reference), the ORs (95% CI) were 1.00 (0.86, 1.15), 1.19 (1.03,1.38), and 1.25 (1.08,1.45) for Q1, Q3, and Q4, respectively. A similar pattern was observed when analyses were conducted for ages < 65 vs. 65+ separately, but it was weaker for those aged 65+. Results from the jointed distribution analyses indicated that moderate weight loss might increase risk for atherosclerosis among participants with obese BMI at baseline, but not for those with cardiovascular event status at baseline. Weight gain, however, would increase risk for atherosclerosis regardless of cardiovascular event status, or overweight/obese BMI at baseline.

Immunotherapy targeting isoDGR-protein damage extends lifespan in a mouse model of protein deamidation.

Aging results from the accumulation of molecular damage that impairs normal biochemical processes. We previously reported that age-linked damage to amino acid sequence NGR (Asn-Gly-Arg) results in "gain-of-function" conformational switching to isoDGR (isoAsp-Gly-Arg). This integrin-binding motif activates leukocytes and promotes chronic inflammation, which are characteristic features of age-linked cardiovascular disorders. We now report that anti-isoDGR immunotherapy mitigates lifespan reduction of Pcmt1-/- mouse. We observed extensive accumulation of isoDGR and inflammatory cytokine expression in multiple tissues from Pcmt1-/- and naturally aged WT animals, which could also be induced via injection of isoDGR-modified plasma proteins or synthetic peptides into young WT animals. However, weekly injection of anti-isoDGR mAb (1 mg/kg) was sufficient to significantly reduce isoDGR-protein levels in body tissues, decreased pro-inflammatory cytokine concentrations in blood plasma, improved cognition/coordination metrics, and extended the average lifespan of Pcmt1-/- mice. Mechanistically, isoDGR-mAb mediated immune clearance of damaged isoDGR-proteins via antibody-dependent cellular phagocytosis (ADCP). These results indicate that immunotherapy targeting age-linked protein damage may represent an effective intervention strategy in a range of human degenerative disorders.

Baroreflex sensitivity is associated with sleep-related breathing problems in adolescents.

OBJECTIVES: To examine the relationship between sleep-related breathing problems (SRBPs) and baroreflex sensitivity (BRS) among adolescents and assesses whether body mass influences this relationship. STUDY DESIGN: SRBPs were assessed in 106 adolescents aged 11-14 years using the Pediatric Sleep Questionnaire. Body mass index (BMI) was calculated, and 5 minutes of continuous beat-to-beat blood pressure (Finapres) and R-R interval were recorded (standard electrocardiogram) after 15 minutes of supine rest. Spectral indices were computed using fast Fourier transform, and transfer function analysis was used to compute BRS. RESULTS: Regression analyses indicate an interaction between BMI and SRBPs (b=-.151, P=.015) on BRS. Graphing the interaction showed that those with higher SRBP scores had lower BRS but that this effect was stronger for those with higher BMI. CONCLUSIONS: Adolescents with elevated SRBP scores had lower BRS. In addition, higher BMI amplified the risk of higher SRBP scores on BRS.

p75 reduces beta-amyloid-induced sympathetic innervation deficits in an Alzheimer's disease mouse model.

Beta-amyloid (Abeta) has adverse effects on brain cells, but little is known about its effects on the peripheral nervous system in Alzheimer's disease (AD). Several lines of in vitro evidence suggest that the neurotrophin receptor p75 mediates or exacerbates Abeta-induced neurotoxicity. Here, we show that p75-deficient sympathetic neurons are more sensitive to Abeta-induced neurite growth inhibition. To investigate the role of p75 in the sympathetic nervous system of AD, p75 mutant mice were crossed with a mouse line of AD model. The majority of p75-deficient AD mice died by 3 weeks of age. The lethality is associated with severe defects in sympathetic innervation to multiple organs. When 1 copy of the BACE1 gene encoding a protein essential in Abeta production was deleted in p75-deficient AD mice, sympathetic innervation was significantly restored. These results suggest that p75 is neuroprotective for the sympathetic nervous system in a mouse model of AD.

Profit versus Quality: The Enigma of Scientific Wellness.

The "best of both worlds" is not often the case when it comes to implementing new health models, particularly in community settings. It is often a struggle between choosing or balancing between two components: depth of research or financial profit. This has become even more apparent with the recent shift to move away from a traditionally reactive model of medicine toward a predictive/preventative one. This has given rise to many new concepts and approaches with a variety of often overlapping aims. The purpose of this perspective is to highlight the pros and cons of the numerous ventures already implementing new concepts, to varying degrees, in community settings of quite differing scales-some successful and some falling short. Scientific wellness is a complex, multifaceted concept that requires integrated experimental/analytical designs that demand both high-quality research/healthcare and significant funding. We currently see the more likely long-term success of those ventures in which any profit is largely reinvested into research efforts and health/healthspan is the primary focus.