The ß 1 -Adrenergic Receptor Contributes to Sepsis-Induced Immunosuppression Through Modulation of Regulatory T-Cell Inhibitory Function.

OBJECTIVES: Although cardiovascular benefits of ß 1 -adrenergic receptor blockade have been described in sepsis, little is known about its impact on the adaptive immune response, specifically CD4 T cells. Herein, we study the effects of ß 1 -adrenergic receptor modulation on CD4 T-cell function in a murine model of sepsis. DESIGN: Experimental study. SETTING: University laboratory. SUBJECTS: C57BL/6 mice. INTERVENTIONS: High-grade sepsis was induced by cecal ligation and puncture in wild-type mice (ß 1+/+ ) with or without esmolol (a selective ß 1 -adrenergic receptor blocker) or in ß 1 -adrenergic receptor knockout mice (ß 1-/- ). At 18 hours after surgery, echocardiography was performed with blood and spleen collected to analyze lymphocyte function. MEASUREMENTS AND MAIN RESULTS: At 18 hours, ß 1+/+ cecal ligation and puncture mice exhibited characteristics of high-grade sepsis and three surrogate markers of immunosuppression, namely decreased splenic CD4 T cells, reduced CD4 T-cell proliferation, and increased regulatory T lymphocyte cell proportions. Pharmacologic and genetic ß 1 -adrenergic receptor blockade reversed the impact of sepsis on CD4 T and regulatory T lymphocyte proportions and maintained CD4 T-cell proliferative capacity. ß 1 -adrenergic receptor blocked cecal ligation and puncture mice also exhibited a global decrease in both pro- and anti-inflammatory mediators and improved in vivo cardiovascular efficiency with maintained cardiac power index despite the expected decrease in heart rate. CONCLUSIONS: ß 1 -adrenergic receptor activation enhances regulatory T lymphocyte inhibitory function and thus contributes to sepsis-induced immunosuppression. This can be attenuated by ß 1 -adrenergic receptor blockade, suggesting a potential immunoregulatory role for this therapy in the management of sepsis.

Functional Impairment of Endothelial Colony Forming Cells (ECFC) in Patients with Severe Atherosclerotic Cardiovascular Disease (ASCVD).

Endothelial dysfunction is a key factor in atherosclerosis. However, the link between endothelial repair and severity of atherosclerotic cardiovascular disease (ASCVD) is unclear. This study investigates the relationship between ASCVD, markers of inflammation, and circulating endothelial progenitor cells, namely hematopoietic cells with paracrine angiogenic activity and endothelial colony forming cells (ECFC). Two hundred and forty-three subjects from the TELARTA study were classified according to the presence of clinical atherosclerotic disease. ASCVD severity was assessed by the number of involved vascular territories. Flow cytometry was used to numerate circulating progenitor cells (PC) expressing CD34 and those co-expressing CD45, CD34, and KDR. Peripheral blood mononuclear cells ex vivo culture methods were used to determine ECFC and Colony Forming Unit- endothelial cells (CFU-EC). The ECFC subpopulation was analyzed for proliferation, senescence, and vasculogenic properties. Plasma levels of IL-6 and VEGF-A were measured using Cytokine Array. Despite an increased number of circulating precursors in ASCVD patients, ASCVD impaired the colony forming capacity and the angiogenic properties of ECFC in a severity-dependent manner. Alteration of ECFC was associated with increased senescent phenotype and IL-6 levels. Our study demonstrates a decrease in ECFC repair capacity according to ASCVD severity in an inflammatory and senescence-associated secretory phenotype context.

Telomere length tracking in children and their parents: implications for adult onset diseases.

Adults with comparatively short or long leukocyte telomere length (LTL) typically continue to display comparatively short or long LTL throughout life. This LTL tracking stems from the inability of person-to-person variation in age-dependent LTL shortening during adulthood to offset the wide interindividual LTL variation established prior to adult life. However, LTL tracking in children is unstudied. This study aimed to examine LTL shortening rates and tracking in children and their parents. Longitudinal study in children (n = 67) and their parents (n = 99), whose ages at baseline were 11.4 ± 0.3 and 43.4 ± 0.4 yr, respectively. LTL was measured by Southern blotting at baseline and ∼14 yr thereafter. LTL displayed tracking in both children [intraclass correlation coefficient (ICC) = 0.905, P < 0.001] and their parents (ICC = 0.856, P < 0.001). The children's rate of LTL shortening was twice that of their parents (40.7 ± 2.5 bp/yr; 20.3 ± 2.1 bp/yr, respectively; P < 0.0001). LTL tracking applies not only to adulthood but also to the second decade of life. Coupled with previous work showing that the interindividual variation in LTL across newborns is as wide as in their parents, these findings support the thesis that the LTL-adult disease connection is principally determined before the second decade of life, perhaps mainly at birth.-Benetos, A., Verhulst, S., Labat, C., Lai, T.-P., Girerd, N., Toupance, S., Zannad, F., Rossignol, P., Aviv, A. Telomere length tracking in children and their parents: implications for adult onset diseases.

Short Leukocyte Telomere Length Precedes Clinical Expression of Atherosclerosis: The Blood-and-Muscle Model.

RATIONALE: Short telomere length (TL) in leukocytes is associated with atherosclerotic cardiovascular disease (ASCVD). It is unknown whether this relationship stems from having inherently short leukocyte TL (LTL) at birth or a faster LTL attrition thereafter. LTL represents TL in the highly proliferative hematopoietic system, whereas TL in skeletal muscle represents a minimally replicative tissue. OBJECTIVE: We measured LTL and muscle TL (MTL) in the same individuals with a view to obtain comparative metrics for lifelong LTL attrition and learn about the temporal association of LTL with ASCVD. METHODS AND RESULTS: Our Discovery Cohort comprised 259 individuals aged 63±14 years (mean±SD), undergoing surgery with (n=131) or without (n=128) clinical manifestation of ASCVD. In all subjects, MTL adjusted for muscle biopsy site (MTLA) was longer than LTL and the LTL-MTLA gap similarly widened with age in ASCVD patients and controls. Age- and sex-adjusted LTL (P=0.005), but not MTLA (P=0.90), was shorter in patients with ASCVD than controls. The TL gap between leukocytes and muscle (LTL-MTLA) was wider (P=0.0003), and the TL ratio between leukocytes and muscle (LTL/MTLA) was smaller (P=0.0001) in ASCVD than in controls. Findings were replicated in a cohort comprising 143 individuals. CONCLUSIONS: This first study to apply the blood-and-muscle TL model shows more pronounced LTL attrition in ASCVD patients than controls. The difference in LTL attrition was not associated with age during adulthood suggesting that increased attrition in early life is more likely to be a major explanation of the shorter LTL in ASCVD patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02176941.

Telomere length dynamics in early life: the blood-and-muscle model.

Telomere length (TL) trajectories in somatic tissues during human growth and development are poorly understood. We examined a blood-and-muscle model during early life, focusing on TL trajectories in leukocytes, representing the highly proliferative hematopoietic system, and skeletal muscle, a minimally proliferative tissue. Leukocyte TL (LTL) and skeletal muscle TL (MTL) were measured in 28 fetuses and 73 children. LTL and MTL were highly variable across individuals (sd: fetal LTL = 0.72 kb, MTL = 0.72 kb; children LTL = 0.81 kb, MTL = 0.82 kb) but were highly correlated within individuals (fetuses, r = 0.76, P < 0.0001; children, r = 0.87, P < 0.0001). LTL was shorter than MTL in fetuses (10.63 vs. 11.01 kb; P = 0.0004) and children (8.46 vs. 9.40 kb; <0.0001). The LTL-MTL gap was smaller in fetuses than children. TL in children was inversely correlated with body mass index (BMI) (LTL: -0.047 ± 0.016 kb/BMI, P < 0.005; MTL: -0.037 ± 0.017 kb/BMI, P = 0.03). We conclude that variations in TL across adults and differences in TL between somatic tissues are largely established in early life. Because TL plays a significant role in aging-related diseases, insight into the factors that fashion TL in somatic tissues during early development should contribute to an understanding of the relationship of TL with these disease and longevity in humans.-Sabharwal, S., Verhulst, S., Guirguis, G., Kark, J. D., Labat, C., Roche, N. E., Martimucci, K., Patel, K., Heller, D. S., Kimura, M., Chuang, D., Chuang, A., Benetos, A., Aviv, A. Telomere length dynamics in early life: the blood-and-muscle model.

Telomere length and age-dependent telomere attrition: the blood-and-muscle model 1.

Short telomere length (TL) is associated with atherosclerotic cardiovascular disease (ACVD) and other age-related diseases. It is unclear whether these associations originate from having inherently short TL or a faster TL attrition before or during disease development. We proposed the blood-and-muscle model to assess TL dynamics throughout life course. Our objective was to measure TL in leukocytes (LTL) and in skeletal muscle (MTL), which served as a proxy of TL at birth. The delta (MTL-LTL) represented life-long telomere attrition. Blood draws and skeletal muscle biopsies were performed on 35 Lebanese individuals undergoing surgery. Following DNA extraction, LTL and MTL were measured by Southern blot. In every individual aged between 30 and 85 years, MTL was longer than LTL. With age, MTL and LTL decreased, but the delta (MTL-LTL) increased by 14 bp/year. We validated the blood-and-muscle model that allowed us to identify TL, TL at birth, and lifelong TL attrition in a cross-sectional study. This model can be used in larger cross-sectional studies to evaluate the association of telomere dynamics with age-related diseases onset and progression.

Prognostic Association of Major Frailty Domain Trajectories With 5-Year Mortality in Very Old Adults: Results From the PARTAGE Cohort Study.

We aimed to identify trajectories of nutrition, cognitive function, and autonomy over time among very old adults and to assess their impact on mortality. A cohort of subjects aged ≥80 years (in 2007-2008) who were followed for 5 years in 72 Italian and French nursing homes was used for post hoc analyses. Body mass index (BMI; weight (kg)/height (m)2), Mini-Mental State Examination (MMSE) score, and Katz Index of Independence in Activities of Daily Living (ADL) score were assessed at 4 time points. Information on vital status was collected during follow-up. Latent trajectory and Cox models were used. In the 710 subjects included, the mean age at inclusion was 88.0 (standard deviation, 4.8) years, and 78.9% were female. We identified 7 composite trajectories based on BMI, MMSE, and ADL values. As compared with the reference group (trajectory 7-stable overweight; preserved cognitive function and autonomy), 2 trajectories presented increased hazards of dying: trajectory 1 (stable overweight; moderately impaired, then declining, cognitive function and autonomy (adjusted hazard ratio = 1.79, 95% confidence interval (CI): 1.26, 2.55)) and trajectory 6 (stable normal BMI; slight cognitive decline; and moderate, then degrading, loss of autonomy (adjusted hazard ratio = 1.67, 95% CI: 1.15, 2.44)). The C-index was 0.81 (95% CI: 0.72, 0.88). Repeated monitoring of BMI, MMSE score, and ADL in very old adults provides trajectories that produce better prognostic information than simple baseline assessment.

A short leucocyte telomere length is associated with development of insulin resistance.

AIMS/HYPOTHESIS: A number of studies have shown that leucocyte telomere length (LTL) is inversely associated with insulin resistance and type 2 diabetes mellitus. The aim of the present longitudinal cohort study, utilising a twin design, was to assess whether shorter LTL predicts insulin resistance or is a consequence thereof. METHODS: Participants were recruited between 1997 and 2000 through the population-based national Danish Twin Registry to participate in the GEMINAKAR study, a longitudinal evaluation of metabolic disorders and cardiovascular risk factors. Baseline and follow-up measurements of LTL and insulin resistance over an average of 12 years were performed in a subset of the Registry consisting of 338 (184 monozygotic and 154 dizygotic) same-sex twin pairs. RESULTS: Age at baseline examination was 37.4 ± 9.6 (mean ± SD) years. Baseline insulin resistance was not associated with age-dependent changes in LTL (attrition) over the follow-up period, whereas baseline LTL was associated with changes in insulin resistance during this period. The shorter the LTL at baseline, the more pronounced was the increase in insulin resistance over the follow-up period (p < 0.001); this effect was additive to that of BMI. The co-twin with the shorter baseline LTL displayed higher insulin resistance at follow-up than the co-twin with the longer LTL. CONCLUSIONS/INTERPRETATION: These findings suggest that individuals with short LTL are more likely to develop insulin resistance later in life. By contrast, presence of insulin resistance does not accelerate LTL attrition.

Role of smooth muscle cell mineralocorticoid receptor in vascular tone.

Identification of the mineralocorticoid receptor (MR) in the vasculature (i.e., endothelial and smooth muscle cells) raised the question of its role in vascular function and blood pressure control. Using a mouse model with conditional inactivation of MR in vascular smooth muscle cell (VSMC) (MR(SMKO)), we have recently shown that the VSMC MR is crucial for aldosterone-salt-induced carotid stiffening. In the present study, we have investigated the specific contribution of the VSMC MR in the regulation of vascular tone in large vessels. In MR(SMKO) mice, contractions induced by potassium chloride and calcium (Ca(2+)) are decreased in the aorta, whereas contraction is normal in response to phenylephrine and caffeine. The difference in response to Ca(2+) suggests that the VSMC-specific deficiency of the MR modifies VSM Ca(2+) signaling but without altering the intracellular Ca(2+) store handling. The relaxation induced by acetylcholine is not affected by the absence of MR. However, the relaxation induced by Ach in the presence of indomethacin and the relaxation induced by sodium nitroprussiate are significantly reduced in MR(SMKO) mice compared to controls. Since endothelial nitric oxide synthase (eNOS) activity is increased in mutant mice, their altered relaxation reflects impairment of the nitric oxide (NO) signaling pathway. In addition to altered NO and Ca(2+) signaling, the activity of myosin light chain and its regulators, myosin light chain kinase (MLCK) and myosin phosphatase (MLCP), is reduced. In conclusion, MR expressed in VSMC is required for NO and Ca(2+) signaling pathways and contractile protein activity leading to an altered contraction/relaxation coupling.

Inactivation of serum response factor contributes to decrease vascular muscular tone and arterial stiffness in mice.

RATIONALE: Vascular smooth muscle (SM) cell phenotypic modulation plays an important role in arterial stiffening associated with aging. Serum response factor (SRF) is a major transcription factor regulating SM genes involved in maintenance of the contractile state of vascular SM cells. OBJECTIVE: We investigated whether SRF and its target genes regulate intrinsic SM tone and thereby arterial stiffness. METHODS AND RESULTS: The SRF gene was inactivated SM-specific knockout of SRF (SRF(SMKO)) specifically in vascular SM cells by injection of tamoxifen into adult transgenic mice. Fifteen days later, arterial pressure and carotid thickness were lower in SRF(SMKO) than in control mice. The carotid distensibility/pressure and elastic modulus/wall stress curves showed a greater arterial elasticity in SRF(SMKO) without modification in collagen/elastin ratio. In SRF(SMKO), vasodilation was decreased in aorta and carotid arteries, whereas a decrease in contractile response was found in mesenteric arteries. By contrast, in mice with inducible SRF overexpression, the in vitro contractile response was significantly increased in all arteries. Without endothelium, the contraction was reduced in SRF(SMKO) compared with control aortic rings owing to impairment of the NO pathway. Contractile components (SM-actin and myosin light chain), regulators of the contractile response (myosin light chain kinase, myosin phosphatase target subunit 1, and protein kinase C-potentiated myosin phosphatase inhibitor) and integrins were reduced in SRF(SMKO). CONCLUSIONS: SRF controls vasoconstriction in mesenteric arteries via vascular SM cell phenotypic modulation linked to changes in contractile protein gene expression. SRF-related decreases in vasomotor tone and cell-matrix attachment increase arterial elasticity in large arteries.

Myocardial oxygen supply and demand imbalance predicts mortality in older nursing home residents: The PARTAGE study.

BACKGROUND: A mismatch between myocardial oxygen supply and demand is the most common cause of ischemic myocardial injury in older persons. The subendocardial viability ratio (SEVR) can usefully estimate the degree of myocardial perfusion relative to left-ventricular workload. The aim of the present study was to evaluate the ability of SEVR to predict long-term mortality in the older population. Additionally, we aimed to identify the SEVR cutoff value best predicting total mortality. METHODS: This is a multicenter, longitudinal study involving a large population of individuals older than 80 years living in nursing homes. Patients with cancer, severe dementia, and very low level of autonomy were excluded from the study. Participants were monitored for 10 years. Adverse outcomes were recorded every 3 months from inclusion to the end of the study. SEVR reflects the balance between subendocardial oxygen supply and demand, and was estimated non-invasively by analyzing the carotid pressure waveform recorded by applanation arterial tonometry. RESULTS: A total of 828 people were enrolled (mean age: 87.7 ± 4.7 years, 78% female). 735 patients died within 10 years and 24 were lost to follow-up. SEVR was inversely associated with mortality at univariate Cox-regression model (risk ratio, 0.683 per unit increase in SEVR; 95% confidence interval (CI) [0.502-0.930], p = 0.015) and in a model including age, sex, body mass index, Activity of Daily Living index and Mini-Mental State Examination score (risk ratio, 0.647; 95% CI [0.472-0.930]). The lowest tertile of SEVR was associated with higher 10-years total mortality than the middle (p < 0.001) and the highest (p < 0.004) tertile. A SEVR cutoff value of 83% was identified as the best predictor of total mortality. CONCLUSIONS: SEVR may be considered as a marker of "cardiovascular frailty." An accurate non-invasive estimation of SEVR could be a useful and independent parameter to assess survival probability in very old adults. TRIAL REGISTRATION: NCT00901355, registered on ClinicalTrials.gov website.

Cardio-ankle vascular index for predicting cardiovascular morbimortality and determinants for its progression in the prospective advanced approach to arterial stiffness (TRIPLE-A-Stiffness) study.

BACKGROUND: The cardio-ankle vascular index (CAVI) measure of arterial stiffness is associated with prevalent cardiovascular risk factors, while its predictive value for cardiovascular events remains to be established. The aim was to determine associations of CAVI with cardiovascular morbimortality (primary outcome) and all-cause mortality (secondary outcome), and to establish the determinants of CAVI progression. METHODS: TRIPLE-A-Stiffness, an international multicentre prospective longitudinal study, enrolled >2000 subjects ≥40 years old at 32 centres from 18 European countries. Of these, 1250 subjects (55% women) were followed for a median of 3.82 (2.81-4.69) years. FINDINGS: Unadjusted cumulative incidence rates of outcomes according to CAVI stratification were higher in highest stratum (CAVI > 9). Cox regression with adjustment for age, sex, and cardiovascular risk factors revealed that CAVI was associated with increased cardiovascular morbimortality (HR 1.25 per 1 increase; 95% confidence interval, CI: 1.03-1.51) and all-cause mortality (HR 1.37 per 1 increase; 95% CI: 1.10-1.70) risk in subjects ≥60 years. In ROC analyses, CAVI optimal threshold was 9.25 (c-index 0.598; 0.542-0.654) and 8.30 (c-index 0.565; 0.512-0.618) in subjects ≥ or <60 years, respectively, to predict increased CV morbimortality. Finally, age, mean arterial blood pressure, anti-diabetic and lipid-lowering treatment were independent predictors of yearly CAVI progression adjusted for baseline CAVI. INTERPRETATION: The present study identified additional value for CAVI to predict outcomes after adjustment for CV risk factors, in particular for subjects ≥60 years. CAVI progression may represent a modifiable risk factor by treatments. FUNDING: International Society of Vascular Health (ISVH) and Fukuda Denshi, Japan.

Tissue factor pathway inhibitor: a new link among arterial stiffness, pulse pressure, and coagulation in postmenopausal women.

OBJECTIVE: To investigate in women older than 60 whether aortic stiffness or pulse pressure (PP) is associated with selected procoagulant or anticoagulant factors and to examine whether pulsatile stretch influences these factors in human vascular smooth muscle cells (VSMCs) in vitro. METHODS AND RESULTS: Aortic pulse wave velocity (PWV) and carotid PP were studied in 123 apparently healthy postmenopausal women. PWV, PP, von Willebrand factor, and free tissue factor pathway inhibitor (TFPI), but not mean arterial pressure, increased with age. Free TFPI and PWV were positively correlated, even after adjustment for age and PP and other confounding parameters. In vitro, 5% or 10% pulsatile stretch (at 1 Hz) enhanced TFPI synthesis and secretion by VSMCs in a time-independent manner (1 to 48 hours) without changes in protein level of smooth muscle myosin heavy chain. Application of 5% static stretch had no effect. CONCLUSIONS: In postmenopausal women, free TFPI increases as vascular wall function deteriorates and PP increases. These findings are supported by the increase in TFPI synthesized by VSMCs in response to cyclic stress in vitro. They suggest that VSMCs require pulsatility to interfere with the coagulation process and highlight the relevance of plasma free TFPI levels to cardiovascular diseases.

Non-Invasive Assessment of Arterial Stiffness: Pulse Wave Velocity, Pulse Wave Analysis and Carotid Cross-Sectional Distensibility: Comparison between Methods.

Background: The stiffening of large elastic arteries is currently estimated in research and clinical practice by propagative and non-propagative models, as well as parameters derived from aortic pulse waveform analysis. Methods: Common carotid compliance and distensibility were measured by simultaneously recording the diameter and pressure changes during the cardiac cycle. The aortic and upper arm arterial distensibility was estimated by measuring carotid−femoral and carotid−radial pulse wave velocity (PWV), respectively. The augmentation index and blood pressure amplification were derived from the analysis of central pulse waveforms, recorded by applanation tonometry directly from the common carotid artery. Results: 75 volunteers were enrolled in this study (50 females, average age 53.5 years). A significant inverse correlation was found between carotid distensibility and carotid−femoral PWV (r = −0.75; p < 0.001), augmentation index (r = −0.63; p < 0.001) and central pulse pressure (r = −0.59; p < 0.001). A strong correlation was found also between the total slope of the diameter/pressure rate carotid curves and aortic distensibility, quantified from the inverse of the square of carotid−femoral PWV (r = 0.67). No correlation was found between carotid distensibility and carotid−radial PWV. Conclusions: This study showed a close correlation between carotid−femoral PWV, evaluating aortic stiffness by using the propagative method, and local carotid cross-sectional distensibility.

Can sitting and lying blood pressure measurements be considered interchangeable in older frail adults?

BACKGROUND: To compare blood pressure (BP) values in the lying and sitting positions, and the effect of orthostatism when moving from each of these positions to the upright position in a geriatric population with various frailty levels. METHODS: In two sub-studies, we included a total of 157 consecutive patients, aged 75+ admitted to the Geriatric Department of Nancy University Hospital. BP and heart rate were sequentially measured three times in 1-min intervals each in lying, sitting and upright positions (Protocol#1, n = 107) or lying and upright positions (Protocol#2, n = 50) with an automatic validated Blood Pressure device. Patients were classified into two increasing frailty status (FS) categories: Low/Moderate (L/M-FS, n = 98) and High (H-FS, n = 59). RESULTS: BP levels were similar in the lying and sitting positions (Protocol#1, SBP 141 ± 22 mmHg vs. 142 ± 21 mmHg, respectively, and DBP 72 ± 12 mmHg vs. 72 ± 12 mmHg, respectively) in both frailty groups. In the H-FS, orthostatic drop of SBP was more pronounced from the lying (22.1 ± 5.8 mmHg, Protocol#2) as compared to the sitting to upright position (9.4 ± 1.9 mmHg, Protocol#1) (p < 0.008), and the same trend was observed for DBP. No such differences were observed in the L-M/FS frailty individuals. CONCLUSIONS: Orthostatic BP changes are more pronounced in the frailest patients when going from lying to the upright position than from the sitting to the upright position. Consequently, in these individuals, lying and sitting BP measurements cannot be interchangeable baseline positions to investigate orthostatic BP effects, and therefore, precise patient positioning should be specified when referring to "baseline BP measurements".

Anti-spike IgG antibody kinetics following the second and third doses of BNT162b2 vaccine in nursing home residents.

BACKGROUND: Duration of post-vaccination protection against COVID-19 in nursing home (NH) residents is a critical issue. The objective of this study was to estimate the duration of the IgG(S) response to the mRNA BNT162b2 vaccine in NH residents with (COV-Yes) or without (COV-No) history of SARS-CoV-2 infection. METHODS: A 574 COV-Yes and COV-No NH residents were included in 2 cohorts: Main (n = 115, median age 87 years) or Confirmatory (n = 459, median age 89 years). IgG(S) quantification was carried out at three different time points following the BNT162b2 vaccine: three (1st) and seven (2nd) months after the 2nd dose, and 1 month after the 3rd dose (3rd quantification) in the Main cohort, and twice (2nd and 3rd) in the Confirmatory cohort. The seroneutralization capacity according to COVID-19 history was also measured in a subgroup of patients. RESULTS: Neutralization capacity was strongly correlated with IgG(S) levels (R2 :76%) without any difference between COV-Yes and COV-No groups for the same levels of IgG(S). After the 2nd dose, duration of the assumed robust protection (IgG(S) >264 BAU/ml) was two-fold higher in the COV-Yes vs. COV-No group: 12.60 (10.69-14.44) versus 5.76 (3.91-8.64) months, with this advantage mainly due to the higher IgG(S) titers after the 2nd dose and secondary to a slower decay over time. After the 3rd dose, duration of robust protection was estimated at 11.87 (9.88-14.87) (COV-Yes) and 8.95 (6.85-11.04) (COV-No) months. These results were similar in both cohorts. CONCLUSIONS AND RELEVANCE: In old subjects living in NH, history of SARS-CoV-2 infection provides a clear advantage in the magnitude and duration of high IgG(S) titers following the 2nd dose. Importantly, the 3rd dose induces a much more pronounced IgG(S) response than the 2nd dose in COV-No subjects, the effect of which should be able to ensure a prolonged protection against severe forms of COVID-19 in these subjects.

Longitudinal Association of Telomere Dynamics with Obesity and Metabolic Disorders in Young Children.

In adults, short leukocyte telomere length (LTL) is associated with metabolic disorders, such as obesity and diabetes mellitus type 2. These associations could stem from early life interactions between LTL and metabolic disorders. To test this hypothesis, we explored the associations between LTL and metabolic parameters as well as their evolution over time in children with or without obesity at baseline. Seventy-three (n = 73) children attending our Outpatient Clinic for the Prevention and Management of Overweight and Obesity in Childhood and Adolescence, aged 2-10 years (mean ± SD: 7.6 ± 2.0 years), were followed for 2 to 4 years. Anthropometric, clinical, and biological (including LTL by Southern blot) measurements were performed annually. Baseline LTL correlated negatively with BMI (p = 0.02), fat percentage (p = 0.01), and blood glucose (p = 0.0007). These associations persisted after adjustments for age and sex. No associations were found between LTL attrition during the follow-up period and any of the metabolic parameters. In young children, obesity and metabolic disturbances were associated with shorter telomeres but were not associated with more pronounced LTL attrition. These results suggest that short telomeres contribute to the development of obesity and metabolic disorders very early in life, which can have a major impact on health.

The endothelial mineralocorticoid receptor regulates vasoconstrictor tone and blood pressure.

Pathophysiological aldosterone (aldo)/mineralocorticoid receptor (MR) signaling has significant effects on the cardiovascular system, resulting in hypertension and cardiovascular remodeling; however, the specific contribution of the vascular MR to blood pressure regulation remains to be established. To address this question, we generated a mouse model with conditional overexpression of the MR in endothelial cells (MR-EC). In basal conditions, MR-EC mice developed moderate hypertension that could be reversed by canrenoate, a pharmacological MR antagonist. MR-EC mice presented increased contractile response of resistance arteries to vasoconstrictors (phenylephrine, thromboxane A(2) analog, angiotensin II, and endothelin 1) in the absence of vascular morphological alterations. The acute blood pressure response to angiotensin II or endothelin 1 infusion was increased in MR-EC mice compared with that in littermate controls. These observations demonstrate that enhanced MR activation in the endothelium generates an increase in blood pressure, independent of stimulation of renal tubular Na(+) transport by aldo/MR or direct activation of smooth muscle MR and establish one mechanism by which endothelial MR activation per se may contribute to impaired vascular reactivity.

Telomere Length in Valve Tissue Is Shorter in Individuals With Aortic Stenosis and in Calcified Valve Areas.

BACKGROUND: Short telomere length (TL) is associated with age-related diseases, in particular cardiovascular diseases. However, whether the onset and course of aortic stenosis (AS) is linked to TL in aortic valves remains unknown. OBJECTIVES: To assess telomere dynamics (TL and telomerase activity) in aortic valves and the possible implication of TL in onset and course of AS. METHODS: DNA was extracted from aortic valves obtained from 55 patients (78.2% men; age, 37-79 years), who had undergone replacement surgery due to AS (AS group, n = 32), aortic valve regurgitation and aortic dilation (Non-AS group, n = 23). TL was measured by telomere restriction fragment analysis (TRF) in calcified and non-calcified aortic valve areas. Telomerase activity was evaluated using telomerase repeat amplification protocol (TRAP) in protein extracts from non-calcified and calcified areas of valves obtained from 4 additional patients (50% men; age, 27-70 years). RESULTS: TL was shorter in calcified aortic valve areas in comparison to non-calcified areas (n = 31, 8.58 ± 0.73 kb vs. 8.12 ± 0.75 kb, p < 0.0001), whereas telomerase activity was not detected in any of those areas. Moreover, patients from AS group displayed shorter telomeres in non-calcified areas than those from the Non-AS group (8.40 ± 0.64 kb vs. 8.85 ± 0.65, p = 0.01). CONCLUSIONS: Short telomeres in aortic valves may participate in the development of AS, while concurrently the calcification process seems to promote further local decrease of TL in calcified areas of valves.

A genetic determinant of VEGF-A levels is associated with telomere attrition.

Telomere length (TL) is a hallmark of cellular aging and is associated with chronic diseases development. The vascular endothelial growth factor A (VEGF-A), a potent angiogenesis factor, is implicated in the pathophysiology of many chronic diseases. The aim of the present study was to investigate the associations between VEGF-A and TL. TL in leukocytes (LTL) and skeletal muscle (MTL) were measured, 10 VEGF-related polymorphisms genotyped, and VEGF-A plasma concentrations determined in 402 individuals from the TELARTA cohort. LTL/MTL ratio was calculated as an estimate of lifelong TL attrition. Associations between VEGF-A variants and levels, and TL parameters were investigated. We identified one significant association between the minor allele (T) of rs6993770 variant and LTL/MTL ratio (P=0.001143, ß=0.0148, SE=0.004516). The rs6993770 is an intronic variant of the ZFPM2 gene, which is involved in haematopoiesis and the identified association with increased telomere attrition could be due to increased haematopoiesis. No significant epistatic interaction was identified, and no association was found between levels of VEGF-A and any of assessed phenotypes. We identified a potential common genetic regulation between VEGF-A and telomere length attrition that could be explained by mechanisms of increased hematopoiesis and production of platelets. VEGF-A and TL could play an important role in personalized medicine of chronic diseases and identification of molecular links between them can promote the understanding of their complex implications.