Thyroid hormone levels within reference range are associated with heart rate, cardiac structure, and function in middle-aged men and women

Background: Triiodothyronine (T3) has many effects on the heart, and marked changes in cardiac function and structure occur in patients with (subclinical) thyroid disease. We investigated whether between-subject variation in thyroid hormone levels within the euthyroid range is also associated with heart rate and echocardiographic heart function and structure. Methods: Subjects were selected from the Asklepios study (n=2524), a population-representative random sample of patients aged between 35 and 55 years, free from overt cardiovascular disease at baseline. Analyses were restricted to 2078 subjects (1013 women and 1065 men), not using antihypertensive or thyroid medication nor having antithyroperoxidase antibody levels above clinical cut-off or thyrotropin (TSH) levels outside the reference range. All subjects were phenotyped in-depth and underwent comprehensive echocardiography, including diastolic evaluation. Thyroid function parameters were determined by automated electrochemiluminescence. Results: Heart rate was robustly positively associated with (quartiles of) free T3 (FT3) and T3, both in subjects with TSH levels within reference (0.27-4.2 μU/L) and in narrow TSH range (0.5-2.5 μU/L; p<0.0001). FT3 and T3 were negatively associated with left ventricular (LV) end-diastolic volume but positively associated with relative wall thickness. Total T3 (TT3) was associated with enhanced ventricular contraction (as assessed by tissue Doppler imaging). Free thyroxine, FT3, and TT3 were positively associated with late ventricular filling, and TT3 was associated with early ventricular filling. Conclusion: We have demonstrated a strong positive association between thyroid hormone levels within the euthyroid range and heart rate, and more subtle effects on cardiac function and structure. More specifically, we suggest a smaller LV cavity size (with increased relative wall thickness), an enhanced atrial and ventricular contraction, and LV relaxation with higher circulating thyroid hormones. These results illustrate that variation in thyroid hormone levels, even within the reference range, exerts effects on the heart

Triiodothyronine and free thyroxine levels are differentially associated with metabolic profile and adiposity-related cardiovascular risk markers in euthyroid middle-aged subjects

Background: We previously showed that in healthy young men a less favorable body composition is associated with higher FT3 levels within the euthyroid range. Besides, a higher FT3-to-FT4 ratio has been related to a less favorable metabolic phenotype and more placental growth in pregnant women. In the present study, we therefore investigated whether serum TSH, thyroid hormone levels and the FT3-to-FT4 ratio are associated with metabolic and adiposity-related cardiovascular risk markers in a healthy population of middle-aged euthyroid men and women. Methods: Thyroid parameters were measured in 2524 generally healthy subjects from the Asklepios study (35-55yrs, mean age 46 years). Analyses were restricted to 2315 subjects (1138 women and 1177 men), not using thyroid medication, not having anti-TPO levels above clinical cut-off values nor TSH levels outside the reference range (0.27-4.2 mU/L). Twenty-seven percent of the women and 47.5% of the men were overweight, while 13% of women and 17% of men were obese. Twenty percent of the subjects were active smokers. Serum thyroid function parameters were determined by electrochemiluminescence. Results: (F) T3 and the FT3-to-FT4 ratio were positively related to BMI, waist circumference and components of the metabolic syndrome, i.e. triglycerides, systolic and diastolic blood pressure and fasting plasma glucose, and negatively with HDL-cholesterol levels, whereas FT4 was negatively associated to BMI, waist circumference and triglycerides (all p-values <0.001). TSH related positively to total cholesterol levels (p<0.01), triglycerides and to systolic and diastolic blood pressure (all p<0.001). The FT3-to-FT4 ratio was further positively associated to the adiposity-related inflammation markers interleukin-6 (IL6) and high-sensitive CRP (hs-CRP) and to pulse wave velocity. All associations were adjusted for sex, age, height and smoking and most associations persisted after additional adjustment for weight or waist circumference. Conclusion: In healthy euthyroid middle-aged men and women, higher (F) T3 levels, lower FT4 levels and thus a higher FT3-to-FT4 ratio are consistently associated with various markers of unfavorable metabolic profile and cardiovascular risk

A prospective cohort study assessing clinical referral management & workforce allocation within a UK regional medical genetics service

Abstract Ensuring patient access to genomic information in the face of increasing demand requires clinicians to develop innovative ways of working. This paper presents the first empirical prospective observational cohort study of UK multi-disciplinary genetic service delivery. It describes and explores collaborative working practices including the utilisation and role of clinical geneticists and non-medical genetic counsellors. Six hundred and fifty new patients referred to a regional genetics service were tracked through 850 clinical contacts until discharge. Referral decisions regarding allocation of lead health professional assigned to the case were monitored, including the use of initial clinical contact guidelines. Significant differences were found in the cases led by genetic counsellors and those led by clinical geneticists. Around a sixth, 16.8% (109/650) of referrals were dealt with by a letter back to the referrer or re-directed to another service provider and 14.8% (80/541) of the remaining patients chose not to schedule an appointment. Of the remaining 461 patients, genetic counsellors were allocated as lead health professional for 46.2% (213/461). A further 61 patients did not attend. Of those who did, 86% (345/400) were discharged after one or two appointments. Genetic counsellors contributed to 95% (784/825) of total patient contacts. They provided 93.7% (395/432) of initial contacts and 26.8% (106/395) of patients were discharged at that point. The information from this study informed a planned service re-design. More research is needed to assess the effectiveness and efficiency of different models of collaborative multi-disciplinary working within genetics services. Keywords (MeSH terms) Genetic Services, Genetic Counseling, Interdisciplinary Communication, Cohort Studies, Delivery of Healthcare, Referral and Consultation

The Rotterdam Study: 2012 objectives and design update

The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, oncological, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in over a 1,000 research articles and reports (see www.erasmus-epidemiology.nl/rotterdamstudy). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

Sepsis and septic shock: pathophysiological and cardiovascular background as basis for therapy

Introduction: Sepsis and septic shock are common causes for admission to intensive care units. The morbidity and mortality remain unacceptably high despite the advanced treatments. Objectives: To review the most commonly reported underlying mechanisms of sepsis and septic shock, besides discussion of sepsis-induced cardiovascular dysfunction. Therapeutic strategies for sepsis-induced myocardial depression are briefly discussed. Data synthesis: The development of sepsis and septic shock is multifactorial. Two major mechanisms contribute to the haemodynamic collapse. The extrinsic and intrinsic mechanisms induce a complex cascade which results in the release of pro- and anti-inflammatory mediators. Sepsis develops when the initial, appropriate host response to an infection becomes amplified and then dysregulated Leading to haemodynamic and circulatory changes. The pro-inflammatory mediators tumour necrosis factor alpha, interleukin-1 beta and nitric oxide play a significant role in sepsis-related hypotension, shock and depression of cardiomyocyte contractility. Septic cardiac dysfunction can be explained by various mechanisms: changes in circulating volume, down-regulation of beta-adrenergic receptors, depressed post-receptor signalling pathways, reduced calcium release from the sarcoplasmic reticulum and impaired electromechanical coupling and reduced calcium sensibility at the myofibrillar level. Mitochondrial derangement seems to be of great importance in tissue injury and sepsis-associated multi organ failure. There is no consistent protocol for treating sepsis and septic shock. Guidelines include early goal-directed therapy, source control and haemodynamic supportive measures. Conclusion: Further studies are needed to distinguish the importance of these various mechanisms: We-recommend that further investigational work should focus on the recovery of the mitochondria-related bio-energetic shut down as the mitochondria could play a key role in the understanding of apoptosis and protective measures. Understanding the pathophysiology of sepsis and septic shock will inevitably lead to a more accurate treatment of these still too often fatal syndromes

Feasibility and agreement of a novel combined echocardiographic method to measure global longitudinal strain and strain rate compared to speckle tracking and tissue Doppler imaging

Background: Currently, two echocardiographic techniques are used to measure deformation: tissue Doppler imaging (TDI) and speckle tracking echocardiography (STE). Recently, a technique combining STE and TDI (on TDI overlay images) has become available, allowing derivation of STE/TDI results from a single acquisition/reading (combined-STE/combined-TDI). We tested the feasibility and agreement of this novel technique to measure left ventricular deformation in the general population compared to STE and TDI. Methods: We examined a subsample of 106 consecutive subjects of the Asklepios Study, a population-based random sample of male/female volunteers without overt clinical disease (mean age: 55.9 years). Left ventricular deformation measurements were assessed with transthoracic echocardiography using the combined method, STE and TDI. Results: Almost all deformation parameters significantly differed between all methods. Global systolic longitudinal strain (GS) and strain rate (GSRs) values measured by combined-TDI were significantly higher (GS -17.2% +/- 3.0, GSRs -0.9 s(-1) +/- 0.2) compared to TDI (GS -21.1% +/- 2.2, GSRs -1.3 s(-1) +/- 0.2). Measurements by combined-STE were significantly lower (GS -19.1% +/- 2.9, GSRs -1.0 s(-1) +/- 0.2) compared to STE (GS -18.2% +/- 3.0, GSRs -0.9 s(-1) +/- 0.1). Overall, the smallest differences and highest agreement were observed between STE and combined-STE (GS r = 0.84, p < .001; GSRs r = 0.70, p < .001). Conclusions: The comparison of methods showed different values and poor agreement between the echocardiographic modalities. Regrettably, the combined method does not make it possible to obtain in a single image/measurement results that are comparable to STE and TDI data in the general population