N-Glycosylation Profiles of Immunoglobulin G and Future Cardiovascular Events.

BACKGROUND: Posttranslational glycosylation of IgG can modulate its inflammatory capacity through structural variations. We examined the association of baseline IgG N-glycans and an IgG glycan score with incident cardiovascular disease (CVD). METHODS: IgG N-glycans were measured in 2 nested CVD case-control studies: JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; NCT00239681; primary prevention; discovery; Npairs=162); and TNT trial (Treating to New Targets; NCT00327691; secondary prevention; validation; Npairs=397). Using conditional logistic regression, we investigated the association of future CVD with baseline IgG N-glycans and a glycan score adjusting for clinical risk factors (statin treatment, age, sex, race, lipids, hypertension, and smoking) in JUPITER. Significant associations were validated in TNT, using a similar model further adjusted for diabetes. Using least absolute shrinkage and selection operator regression, an IgG glycan score was derived in JUPITER as a linear combination of selected IgG N-glycans. RESULTS: Six IgG N-glycans were associated with CVD in both studies: an agalactosylated glycan (IgG-GP4) was positively associated, while 3 digalactosylated glycans (IgG glycan peaks 12, 13, 14) and 2 monosialylated glycans (IgG glycan peaks 18, 20) were negatively associated with CVD after multiple testing correction (overall false discovery rate <0.05). Four selected IgG N-glycans comprised the IgG glycan score, which was associated with CVD in JUPITER (adjusted hazard ratio per glycan score SD, 2.08 [95% CI, 1.52-2.84]) and validated in TNT (adjusted hazard ratio per SD, 1.20 [95% CI, 1.03-1.39]). The area under the curve changed from 0.693 for the model without the score to 0.728 with the score in JUPITER (PLRT=1.1×10-6) and from 0.635 to 0.637 in TNT (PLRT=0.017). CONCLUSIONS: An IgG N-glycan profile was associated with incident CVD in 2 populations (primary and secondary prevention), involving an agalactosylated glycan associated with increased risk of CVD, while several digalactosylated and sialylated IgG glycans associated with decreased risk. An IgG glycan score was positively associated with future CVD.

Influenza vaccination and use of lipid lowering therapies in adults with atherosclerotic cardiovascular disease: An analysis of the Behavioral Risk Factor Surveillance System (BRFSS).

BACKGROUND: Influenza vaccination and lipid lowering therapy (LLT) are evidence-based interventions with substantial benefit for individuals with established atherosclerotic cardiovascular disease (ASCVD). However, levels of influenza immunization and LLT use are low, possibly due to pervasive fear-based misinformation uniquely targeting vaccines and LLT. Whether being unvaccinated for influenza predicts lower utilization of LLT is unknown. OBJECTIVES: We tested the hypothesis that American adults with ASCVD who are unvaccinated for influenza have lower use of LLT even after accounting for traditional factors associated with underuse of preventive therapies. METHODS: We pooled 2017, 2019, and 2021 survey data from the Behavioral Risk Factor Surveillance System (BRFSS), and selected respondents aged 40 to 75 years with self-reported ASCVD. We used logistic regression models adjusted for potential confounders to examine the association between influenza vaccination and self-reported LLT use. We performed a sensitivity analysis with multiple imputation to account for missing data. All analyses accounted for complex survey weighting. RESULTS: Of 66,923 participants with ASCVD, 55% reported influenza vaccination in the last year and 76% reported using LLT. Being unvaccinated for influenza was associated with lower odds of LLT use (OR 0.54; 95% CI 0.50, 0.58; P< .001). In a multivariable regression model adjusting for demographics and comorbidities, this association remained statistically significant (aOR 0.58, 95% CI 0.52, 0.64, P < .001). After additional adjustment for preventive care engagement, health care access, and use patterns of other cardiovascular medications this association persisted (aOR 0.66; 95% CI 0.60, 0.74; P < .001). There were no significant differences across subgroups, including those with and without hyperlipidemia. CONCLUSIONS: Unvaccinated status for influenza was independently associated with 34% lower odds of LLT use among American adults with ASCVD after adjustment for traditional factors linked to underuse of preventive therapies. This finding identifies a population with excess modifiable ASCVD risk, and supports investigation into nontraditional mechanisms driving underuse of preventive therapies, including fear-based misinformation.

Association of Physical Activity With Bioactive Lipids and Cardiovascular Events.

BACKGROUND: To clarify the mechanisms underlying physical activity (PA)-related cardioprotection, we examined the association of PA with plasma bioactive lipids (BALs) and cardiovascular disease (CVD) events. We additionally performed genome-wide associations. METHODS: PA-bioactive lipid associations were examined in VITAL (VITamin D and OmegA-3 TriaL)-clinical translational science center (REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01169259; N=1032) and validated in JUPITER (Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin)-NC (REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT00239681; N=589), using linear models adjusted for age, sex, race, low-density lipoprotein-cholesterol, total-C, and smoking. Significant BALs were carried over to examine associations with incident CVD in 2 nested CVD case-control studies: VITAL-CVD (741 case-control pairs) and JUPITER-CVD (415 case-control pairs; validation). RESULTS: We detected 145 PA-bioactive lipid validated associations (false discovery rate <0.1). Annotations were found for 6 of these BALs: 12,13-diHOME, 9,10-diHOME, lysoPC(15:0), oxymorphone-3b-D-glucuronide, cortisone, and oleoyl-glycerol. Genetic analysis within JUPITER-NC showed associations of 32 PA-related BALs with 22 single-nucleotide polymorphisms. From PA-related BALs, 12 are associated with CVD. CONCLUSIONS: We identified a PA-related bioactive lipidome profile out of which 12 BALs also had opposite associations with incident CVD events.

Diabetes and subclinical hypothyroidism on heart rate variability.

BACKGROUND: We aimed to analyse if the effects of coexistent diabetes and subclinical hypothyroidism extend to the cardio autonomic nervous system, using heart rate variability baseline data from the Brazilian Longitudinal Study of Adult Health. MATERIALS AND METHODS: Heart rate variability analyses were performed by linear time and frequency domains in 5-minute time series collected in the supine position. The associations of diabetes and subclinical hypothyroidism with the lowest quartile group for heart rate and the highest quartile group for each heart rate variability parameter were analysed using additive and multiplicative terms in logistic models. For the first approach, the subsample was categorized into four groups: subjects without diabetes and normal thyroid function (controls); subjects without diabetes and subclinical hypothyroidism; patients with diabetes and normal thyroid function; and patients with diabetes and subclinical hypothyroidism. For the interaction alnalysis, diabetes and subclinical hypothyroidism diagnoses were included in separate, along with a multiplicative interaction term between them. RESULTS: Point odds ratio estimates for the 4th quartiles of heart rate, and 1st quartiles of all heart rate variability measurements were higher for subjects with combined diabetes and subclinical hypothyroidism than for diabetes only, independently of main sociodemographic and clinical variables (HR: 8.33 vs 2.63; SDNN: 2.59 vs 1.61; RMSSD: 2.37 vs 1.42; LF: 2.83 vs 1.71; HF: 3.06 vs 1.39), but not independently of HbA1c and TSH. Only the interaction term for the association with heart rate, adjusted for sociodemographic and clinical variables, had borderline statistical significance. CONCLUSION: Diabetes and subclinical hypothyroidism exert a potential joint impact on cardiac autonomic control, showed by additive effects between diabetes and subclinical hypothyroidism, as well as a significant interaction term for the association with heart rate.

Decreased heart rate variability as a predictor for diabetes-A prospective study of the Brazilian longitudinal study of adult health.

AIM: To investigate whether heart rate variability (HRV) is a predictor for the incidence of diabetes in a 4-year follow-up. MATERIALS AND METHODS: The HRV of 9192 participants free of diabetes was analysed in time and frequency domains and stratified based on the reference values presented in the literature. The participants were then allocated to one of three groups, according to age-specific value distributions for each HRV domain: lower than the 25th percentile, between the 25th and 75th percentiles, and higher than the 75th percentile. The association between HRV and diabetes incidence at 4-year follow-up was analysed using Poisson regression models with robust estimator. RESULTS: Six hundred thirty-four participants (6.90%) developed diabetes within 4 years and five out of six HRV analysed indices showed increased relative risk of developing diabetes associated with low HRV: SDNN (RR = 1.29; 95% CI, 1.09-1.52; .003), pNN50 (RR = 1.33; 95% CI, 1.11-1.58; .001), RMSSD (RR = 1.29; 95% CI, 1.09-1.53; .004), LF (RR = 1.25; 95% CI, 1.05-1.48; .012), and HF (RR = 1.39; 95% CI, 1.16-1.63; .001). CONCLUSIONS: This study suggests that both overall variability and changes in parasympathetic modulation precede the incidence of diabetes. For four HRV indices below the 25th percentile, the risk for incident diabetes was 68% higher than for those participants who presented none. We concluded that HRV is an independent risk predictor of diabetes in a 4-year period.

Fractal correlations and linear analyses of heart rate variability in healthy young people with different levels of physical activity.

Changes in cardiac autonomic regulation, expressed by increased sympathetic activity and decreased heart rate variability, have an important relationship with the onset of lethal cardiac phenomena. Therefore, we aimed to evaluate the cardiac autonomic behaviour in young people according to their level of physical activity. Through the International Physical Activity Questionnaire, 55 healthy young non-smokers with no history of previous diseases and whose parents did not suffer from metabolic syndrome were assessed and divided into groups: sedentary (n=12), insufficiently active (n=16), active (n=14), and very active (n=13). We collected respiratory rate, systolic and diastolic blood pressure at rest, and body mass index. Subjects remained supine at rest, and without mental stress for 15 minutes in a controlled environment. Using a cardiofrequency meter (Polar® RS800CX), data were analysed in the time domain, frequency domain, and detrended fluctuation analysis. For the sedentary group, the mean RR and rMSSD were significantly lower, and the insufficiently active group showed higher means, but significantly only for rMSSD. The insufficiently active group showed in the detrended fluctuation analysis that α2 was significantly lower compared with the sedentary, active, and very active groups. We conclude that young, healthy, sedentary individuals present an increased heart rate and that insufficiently active individuals present a decreased fractal correlation and increased parasympathetic activity.

Reduced heart-rate variability and increased risk of hypertension-a prospective study of the ELSA-Brasil.

Although autonomic disturbances are known to precede hypertension onset, the risks underlying different ranges of blood pressure and impaired cardiac autonomic modulation are still unknown. This study aimed to identify the risk of hypertension incidence related to low heart-rate variability profile in normotensive blood pressure subcategories: normal (<120/80 mmHg) and prehypertension (120/80-139/89 mmHg) in a 4-year follow-up. 7665 participants free of hypertension at baseline were examined. They were allocated into one of two groups (

Relationship between heart rate variability and carotid intima-media thickness in the Brazilian Longitudinal Study of Adult Health - ELSA-Brasil.

BACKGROUND: Both increased carotid intima-media thickness (cIMT) and low heart rate variability (HRV) have been associated with cardiovascular mortality and morbidity. Thus, the aim of this study was to investigate whether cardio autonomic alterations are accompanied or not by subclinical atherosclerosis in participants of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). METHODS: cIMT measures and 5-min HRV analyses were performed in apparently healthy adults. Heart rate variability was evaluated by linear time and frequency domain analyses. cIMT was defined as the average between the mean left and mean right cIMT values and was analysed as continuous and categorized variables (P≥75 or P<75). Multiple linear models using continuous variables and multivariate logistic regression with categorized cIMT and HRV quartiles were performed. RESULTS: Out of 7256 participants eligible for analyses, 23·4% presented cIMT ≥ 75th percentile. Heart rate variability variables were reduced in cIMT ≥ P75 in comparison with cIMT < P75: SDNN 33·0 versus 37·0 ms, P<0·001; RMSSD 22·0 versus 26·0 ms, P<0·001; LF 191·0 versus 260·0 ms2 , P<0·001; HF 164·0 versus 238·5 ms2 , P<0·001. In crude analysis, an increased odds ratio for cIMT ≥ P75 was verified within the lowest two quartiles of LF and HF, but significances did not remain after adjustments for anthropometric and clinical variables. CONCLUSIONS: Considering the entire sample, subjects with cIMT ≥ P75 presented lower HRV values, but no independent relationships were detected between cIMT and HRV after multivariate adjustment.

Linear and nonlinear analyses of heart rate variability following orthostatism in subclinical hypothyroidism.

Subclinical hypothyroidism (SCHypo) is associated with autonomic disturbances that can interfere in physiological responses. This study was designed to evaluate linear and nonlinear variables of heart rate variability (HRV) following postural change, comparing subjects with SCHypo to euthyroid subjects.HRV analyses were performed in 5-minute time series collected in the supine and standing positions from a subsample of 855 participants of the ELSA-Brasil study. The cardiac autonomic nervous function was evaluated by linear time and frequency domain analyses (SDNN, RMSSD, LFms, HFms, and LF/HF ratio) as well as by nonlinear symbolic dynamics (0, 1, and 2 V).After exclusions, 509 (92.0%) euthyroid and 44 (8.0%) SCHypo participants were eligible for analyses. At the baseline supine rest measurement, the 0 V symbolic pattern was higher (27.7 vs 25.4, P = .02) and 2 V was lower (18.0 vs 22.9, P = .02) than in the euthyroid group. Comparing the variation between positions, the 0 V pattern showed a lower delta in SCHypo than in Euthyroid subjects (8.0 vs 10.8%, P = .04).SCHypo presented lower sympathetic and parasympathetic tonus at rest and a blunted sympathetic response to active postural change, marked by reduced variation in the 0 V of symbolic analysis (SA). Additionally, it is suggested that SA of HR dynamics is an alternative and, possibly, a more sensitive method for cardiac autonomic assessment following orthostatism in this population.