Arjola Bano

Estrogen receptor β actions in the female cardiovascular system: A systematic review of animal and human studies

Five medical databases were searched for studies that assessed the role of ERβ in the female cardiovascular system and the influence of age and menopause on ERβ functioning. Of 9472 references, 88 studies met our inclusion criteria (71 animal model experimental studies, 15 human model experimental studies and 2 population based studies). ERβ signaling was shown to possess vasodilator and antiangiogenic properties by regulating the activity of nitric oxide, altering membrane ionic permeability in vascular smooth muscle cells, inhibiting vascular smooth muscle cell migration and proliferation and by regulating adrenergic control of the arteries. Also, a possible protective effect of ERβ signaling against left ventricular hypertrophy and ischemia/reperfusion injury via genomic and non-genomic pathways was suggested in 27 studies. Moreover, 5 studies reported that the vascular effects of ERβ may be vessel specific and may differ by age and menopause status. ERβ seems to possess multiple functions in the female cardiovascular system. Further studies are needed to evaluate whether isoform-selective ERβ-ligands might contribute to cardiovascular disease prevention.

Association of Thyroid Function With Life Expectancy With and Without Cardiovascular Disease: The Rotterdam Study

Importance Variations in thyroid function within reference ranges are associated with an increased risk of cardiovascular disease (CVD) and mortality. However, the impact of thyroid function on life expectancy (LE) and the number of years lived with and without CVD remains unknown. Objective To investigate the association of thyroid function with total LE and LE with and without CVD among euthyroid individuals. Design, Setting, and Participants The Rotterdam Study, a population-based, prospective cohort study. We included participants without known thyroid disease and with thyrotropin and free thyroxine (FT4) levels within the reference ranges. Main Outcomes and Measures Multistate life tables were used to calculate total LE and LE with and without CVD among thyrotropin and FT4 tertiles. Life expectancy estimates in men and women aged 50 years and older were obtained using prevalence, incidence rates, and hazard ratios for 3 transitions (healthy to CVD, healthy to death, and CVD to death), adjusting for sociodemographic and cardiovascular risk factors. Results The mean (SD) age of the 7785 participants was 64.7 (9.8) years, and 52.5% were women. Over a median follow-up of 8.1 (interquartile range, 2.7-9.9) years, we observed 789 incident CVD events and 1357 deaths. Compared with those in the lowest tertile, men and women in the highest thyrotropin tertile lived 2.0 (95% CI, 1.0 to 2.8) and 1.4 (95% CI, 0.2 to 2.4) years longer, respectively, of which, 1.5 (95% CI, 0.2 to 2.6) and 0.9 (95% CI, −0.2 to 2.0) years longer without CVD. Compared with those in the lowest tertile, the difference in life expectancy for men and women in the highest FT4 tertile was −3.2 (95% CI, −5.0 to −1.4) and −3.5 (95% CI, −5.6 to −1.5) years, respectively, of which, −3.1 (95% CI, −4.9 to −1.4) and −2.5 (95% CI, −4.4 to −0.7) years without CVD. Conclusions and Relevance At the age of 50 years, participants with low-normal thyroid function live up to 3.5 years longer overall and up to 3.1 years longer without CVD than participants with high-normal thyroid function. These findings provide supporting evidence for a reevaluation of the current reference ranges of thyroid function and can help inform preventive and clinical care.

Thyroid Function and the Risk of Atherosclerotic Cardiovascular Morbidity and Mortality: The Rotterdam Study

Rationale: Thyroid hormones have been linked with various proatherogenic and antiatherogenic processes. However, the relationship of thyroid function with manifestations of atherosclerosis remains unclear. Objective: To investigate the association of thyroid function with atherosclerosis throughout its spectrum; that is, subclinical atherosclerosis, incident atherosclerotic cardiovascular (ASCV) events, and ASCV mortality. Methods and Results: This population-based study was embedded within the Rotterdam Study. The risk of atherosclerosis was evaluated by measuring (1) presence of subclinical atherosclerosis, assessed by coronary artery calcification score >100 AU; (2) ASCV events, defined as fatal and nonfatal myocardial infarction, other coronary heart disease mortality, or stroke; (3) ASCV mortality, defined as death because of coronary heart disease and cerebrovascular or other atherosclerotic diseases. Associations of thyroid-stimulating hormone and free thyroxine with the outcomes were assessed through logistic regression and Cox proportional hazard models, adjusted for potential confounders, including cardiovascular risk factors. A total of 9420 community-dwelling participants (mean age±SD, 64.8±9.7 years) were included. During a median follow-up of 8.8 years (interquartile range, 4.5–11.8 years), 934 incident ASCV events and 612 ASCV deaths occurred. Free thyroxine levels were positively associated with high coronary artery calcification score (odds ratio, 2.28; 95% confidence interval, 1.30–4.02) and incident ASCV events (hazard ratio, 1.87; confidence interval, 1.34–2.59). The risk of ASCV mortality increased in a linear manner with higher free thyroxine levels (hazard ratio, 2.41; confidence interval, 1.68–3.47 per 1 ng/dL) and lower thyroid-stimulating hormone levels (hazard ratio, 0.92; confidence interval, 0.84–1.00 per 1 logTSH). Results remained similar or became stronger among euthyroid participants. Conclusions: Free thyroxine levels in middle-aged and elderly subjects were positively associated with atherosclerosis throughout the whole disease spectrum, independent of cardiovascular risk factors.

High Circulating Free Thyroxine Levels May Increase the Risk of Frailty: The Rotterdam Study

Context Thyroid hormones affect metabolism in various tissues, organs, and systems. However, the overall impact of thyroid function on an individuals vulnerability to adverse outcomes remains unclear. Objective To investigate the cross-sectional and prospective association of thyroid function with the frailty index, a well-established measure of overall health. Design and Setting The Rotterdam Study, a population-based, prospective cohort study. Participants and Main Outcome Measurements Participants with baseline measurements of thyroid function and the frailty index were eligible. The frailty index was measured at baseline and after a median follow-up time of 10.1 years (interquartile range, 5.7 to 10.8 years). A higher frailty index indicated a worse health state. We assessed the association of thyroid function with frailty at baseline, frailty at follow-up, and frailty changes over time, adjusting for age, sex, cohort, smoking, alcohol, and education. Results We included 9640 participants (mean age, 64.9 years). There was a U-shaped association of thyrotropin (TSH; P < 0.0003) and free thyroxine (FT4; P < 0.0001) with frailty at baseline. There was no association of TSH, but a positive association of FT4 with frailty at follow-up and frailty changes over time (β, 1.22; confidence interval, 0.73 to 1.72 per 1 unit FT4). Conclusion In this population-based study, participants with low and high thyroid function were more likely to be frail than participants with normal thyroid function. However, only those with higher FT4 levels had an increased risk of becoming more frail over time. The identification of FT4 as a potential marker of health deterioration could have future implications regarding the prediction and prevention of frailty.

Gait patterns associated with thyroid function: The Rotterdam Study

Gait is an important health indicator and poor gait is strongly associated with disability and risk of falls. Thyroid dysfunction is suggested as a potential determinant of gait deterioration, but this has not been explored in a population-based study. We therefore investigated the association of thyroid function with gait patterns in 2645 participants from the Rotterdam Study with data available on TSH (thyroid-stimulating hormone), FT4 (free thyroxine) and gait, without known thyroid disease or dementia. The primary outcome was Global gait (standardized Z-score), while secondary outcomes included gait domains (Rhythm, Variability, Phases, Pace, Base of support, Tandem, Turning) and velocity. Gait was assessed by electronic walkway. Multivariable regression models revealed an inverted U-shaped association of TSH (p < 0.001), but no association of FT4 concentrations with Global gait (p = 0.2). TSH levels were positively associated with Base of support (p = 0.01) and followed an inverted U-shaped curve with Tandem (p = 0.002) and velocity (p = 0.02). Clinical and subclinical hypothyroidism were associated with worse Global gait than euthyroidism (β = −0.61; CI = −1.03, −0.18; p = 0.004 and β = −0.13; CI = −0.26, −0.00; p = 0.04, respectively). In euthyroid participants, higher thyroid function was associated with worse gait patterns. In conclusion, both low and high thyroid function are associated with alterations in Global gait, Tandem, Base of support and velocity.

The Association of Autoimmune Thyroid Disease (AITD) with Psoriatic Disease: a prospective cohort study, systematic review and meta-analysis

OBJECTIVE Autoimmune thyroid disease (AITD) and psoriatic disease share auto-immunological components. Few studies have investigated the link between both, yielding inconclusive results. DESIGN We assessed the association of AITD with psoriatic disease in a prospective cohort study and performed a systematic review and meta-analysis. METHODS 8214 participants of the Rotterdam Study (RS) with thyroid peroxidase antibodies (TPO-Abs), thyroid-stimulating hormone (TSH) and/or free thyroxine (FT4) measurements and information on psoriatic disease were included. We performed logistic and Cox regression analyses and a systematic literature search in several electronic databases on AITD and psoriatic disease. We pooled odds ratios (ORs) of included studies using the Mantel-Haenszel method, while adding RS data on prevalent psoriatic disease. RESULTS Within the RS, we found no association between TPO-Ab positivity and psoriatic disease. There was a positive trend between TSH and prevalent psoriatic disease, and between FT4 and incident psoriatic disease, although not significant. Out of 1850 articles identified, seven were included in the systematic review and four in the meta-analysis. The risk of psoriatic disease (pooled OR) was 1.71 (confidence interval (CI): 1.27-2.31) for TPO-Ab positivity, 1.25 (CI: 1.14-1.37) for AITD and 1.34 (CI: 1.16-1.54) respectively, and 1.17 (CI: 1.03-1.32) for hypothyroidism and hyperthyroidism. CONCLUSIONS Our meta-analysis suggests that TPO-Ab positivity, hypothyroidism and hyperthyroidism might be associated with prevalent psoriatic disease. However, there are only few studies with large heterogeneity regarding psoriatic disease definition and indication of publication bias. Additional prospective data are needed to assess the association of AITD with incident psoriatic disease.

Electrocardiographic abnormalities in Chagas disease in the general population: A systematic review and meta-analysis

Background Chagas disease (CD) is a major public health concern in Latin America and a potentially serious emerging threat in non-endemic countries. Although the association between CD and cardiac abnormalities is widely reported, study design diversity, sample size and quality challenge the information, calling for its update and synthesis, which would be very useful and relevant for physicians in non-endemic countries where health care implications of CD are real and neglected. We performed to systematically review and meta-analyze population-based studies that compared prevalence of overall and specific ECG abnormalities between CD and non-CD participants in the general population. Methods Six databases (EMBASE, Ovid Medline, Web of Science, Cochrane Central, Google Scholar and Lilacs) were searched systematically. Observational studies were included. Odds ratios (OR) were computed using random-effects model. Results Forty-nine studies were selected, including 34,023(12,276 CD and 21,747 non-CD). Prevalence of overall ECG abnormalities was higher in participants with CD (40.1%; 95%CIs=39.2-41.0) compared to non-CD (24.1%; 95%CIs=23.5-24.7) (OR=2.78; 95%CIs=2.37-3.26). Among specific ECG abnormalities, prevalence of complete right bundle branch block (RBBB) (OR=4.60; 95%CIs=2.97-7.11), left anterior fascicular block (LAFB) (OR=1.60; 95%CIs=1.21-2.13), combination of complete RBBB/LAFB (OR=3.34; 95%CIs=1.76-6.35), first-degree atrioventricular block (A-V B) (OR=1.71; 95%CIs=1.25-2.33), atrial fibrillation (AF) or flutter (OR=2.11; 95%CIs=1.40-3.19) and ventricular extrasystoles (VE) (OR=1.62; 95%CIs=1.14-2.30) was higher in CD compared to non-CD participants. Conclusions This systematic review and meta-analysis provides an update and synthesis in this field. This research of observational studies indicates a significant excess in prevalence of ECG abnormalities (40.1%) related to T. cruzi infection in the general population from Chagas endemic regions, being the most common ventricular (RBBB and LAFB), and A-V B (first-degree) node conduction abnormalities as well as arrhythmias (AF or flutter and VE). Also, prevalence of ECG alterations in children was similar to that in adults and suggests earlier onset of cardiac disease.

Phytoestrogen supplementation and body composition in postmenopausal women: A systematic review and meta-analysis of randomized controlled trials.

Phytoestrogen-based medications are commonly used by menopausal women, and especially by obese postmenopausal women, to relieve menopausal symptoms. Substitution of animal with soy protein is often used in weight loss regimens, yet the effect of phytoestrogens, the main constituent of soy foods, on body composition is not completely understood. We conducted a systematic review and meta-analysis to investigate the associations between phytoestrogen supplementation and body weight and the main parameters of body composition in postmenopausal women. A literature search was done using 5 electronic databases from inception to April 2018. Randomized controlled trials (RCTs) with postmenopausal women comparing phytoestrogen supplementation followed by usual diet and placebo were included in the present meta-analysis. From 5932 references, we identified 23 RCTs that met our inclusion criteria, with a total of 1880 postmenopausal women. No association was observed between phytoestrogen supplementation and body weight, body mass index, waist and hip circumference, total fat mass or percentage of body fat. However, the use of phytoestrogens supplementation was associated with a slight decrease in waist-hip ratio; the pooled mean difference was -0.01 cm (95%CI: -0.01 to -0.006). In subgroup analysis, we found a modest decrease in body weight with phytoestrogens supplementation compared with placebo in healthy postmenopausal women [pooled mean difference of changes -0.28 kg (95%CI: -0.52 to -0.04)] and in RCTs with a median number of participants of 66 or less [pooled mean difference of changes -0.49 kg (95%CI: -0.87 to -0.11)]. In contrast, phytoestrogen supplementation was associated with increased body weight in postmenopausal women with preexisting metabolic disorders (prediabetes, type 2 diabetes, prehypertension and hyperlipidemia) [pooled mean difference of changes: 0.78 kg (95%CI: 0.53-1.03)]. In addition, there were some indications that some types of phytoestrogens, such as daidzein, but not soy products or isoflavone mix, could lead to modest adverse changes in body composition in menopausal women. Therefore, future studies should investigate the potential adverse effects of phytoestrogen supplementation on body composition among postmenopausal women.

Thyroid function and atrial fibrillation: Is there a mediating role for epicardial adipose tissue?

Background The underlying mechanism of the association between thyroid function and atrial fibrillation (AF) is poorly understood, but epicardial adipose tissue (EAT) could be a promising mediator. Methods In the 1995 participants (mean age 64.5 years) from the population-based Rotterdam Study, we measured thyroid function (thyroid-stimulating hormone, free thyroxine [FT4]) and performed computed tomography to quantify EAT volumes. All participants were followed for the occurrence of AF. We assessed associations of thyroid-stimulating hormone and FT4 with EAT and AF and performed causal mediation analysis to decompose the overall effect of thyroid function on AF with EAT as mediator. Results Higher FT4 levels were associated with larger EAT volumes in persons with large waist circumferences, defined by sex-specific cutoffs (0.08 mL more EAT per 1-SD increase in FT4, 95% CI: 0.02, 0.14), but not in persons with a normal waist circumference. In persons with a large waist circumference, higher FT4 levels were associated with a higher AF risk (hazard ratio 1.50, 95% CI: 1.22, 1.83). We found no evidence of a mediating role of EAT in the association of thyroid function with AF (mediated interaction 1.6%, pure indirect effect 3.2%). The estimate of reference interaction of EAT with thyroid function on AF risk was more substantial (10.8%), but statistically nonsignificant. Conclusions Higher FT4 levels are associated with larger EAT volumes in persons with abdominal obesity. We report no mediating role of EAT in the association of thyroid function with AF, but found evidence for a suggested interaction of FT4 with EAT volumes on AF risk.

Age at natural menopause and life expectancy with and without type 2 diabetes

OBJECTIVE Effective interventions of future health care require a better understanding of the health risks associated with early onset of menopause and diabetes, but the necessary data are scarce. Little quantitative information is available about the combined association of early menopause and diabetes on life expectancy and the number of years lived with and without diabetes. METHODS We included 3,650 postmenopausal women aged 45+ years from the Rotterdam Study, a prospective population-based cohort study. Age at menopause categories were defined as follows: early (≤44 y old), normal (45-54 y old), and late (≥55 y old). For life table calculations, we used prevalence, incidence rates, and hazard ratios for three transitions (free of diabetes to diabetes, free of diabetes to death, and diabetes to death) stratifying by age at menopause categories and adjusting for confounders. RESULTS Compared with late menopause, the difference in life expectancy for women who experienced early menopause was -3.5 (95% CI, -6.6 to -0.8) years overall and -4.6 (95% CI, -8.9 to -0.9) years without diabetes. Compared with age at normal menopause, the difference in life expectancy for women who experienced early menopause was -3.1 (95% CI, -5.1 to -1.1) years overall and -3.3 (95% CI, -6.0 to -0.6) years without diabetes. CONCLUSIONS Women who experienced early menopause lived less long and spent fewer years without diabetes than women who experienced normal or late menopause.