Jens Faber

Plasma Adiponectin, Body Mass Index, and Mortality in Patients With Chronic Heart Failure

Background—Recent studies have suggested that higher body mass index (BMI) is associated with improved prognosis in chronic heart failure (CHF). The adipocytokine adiponectin is inversely associated with BMI, and in healthy subjects, low adiponectin is a predictor of mortality. In a prospective study, we therefore evaluated the association between plasma adiponectin levels and mortality among patients with CHF. Methods and Results—In 195 CHF patients (age 69.3±10.2 years, BMI 27.3±5.2 kg/m2, left ventricular ejection fraction 30±8.9%, mean±SD), plasma adiponectin and N-terminal pro brain natriuretic peptide (NT-proBNP) were measured at baseline. Adiponectin was positively associated with NT-proBNP (&bgr;=0.47, P<0.001), and both biomarkers were negatively associated with BMI (&bgr;=−0.43, P<0.001 for adiponectin and &bgr;=−0.38, P<0.001 for NT-proBNP, respectively) During a median follow-up of 2.6 years, 46 (23.5%) of the patients died. After adjustment for clinical variables associated with CHF severity (age, systolic blood pressure, left ventricular ejection fraction <25%, duration of CHF, and creatinine clearance) and for NT-proBNP, the hazard ratio of mortality for values in the 2 upper tertiles relative to the lowest tertile of adiponectin was 3.23 (P=0.032). BMI predicted mortality independently of clinical parameters of CHF severity (hazard ratio=0.63, P=0.012), but this association became insignificant after additional adjustment for NT-proBNP (hazard ratio=0.74, P=0.13). Conclusions—A high adiponectin level was a predictor of mortality, independent of risk markers of CHF severity, presumably because of its role as a marker for wasting. BMI was also associated with mortality, but a part of this relation may be mediated by adiponectin and NT-proBNP levels.

The spectrum of thyroid disease and risk of new onset atrial fibrillation: a large population cohort study

Objectives To examine the risk of atrial fibrillation in relation to the whole spectrum of thyroid function in a large cohort of patients. Design Population based cohort study of general practice patients identified by linkage of nationwide registries at the individual level. Setting Primary care patients in the city of Copenhagen. Subjects Registry data for 586 460 adults who had their thyroid function evaluated for the first time by their general practitioner during 2000-10 and who were without previously recorded thyroid disease or atrial fibrillation. Main outcome measure Poisson regression models used to estimate risk of atrial fibrillation by thyroid function. Results Of the 586 460 individuals in the study population (mean (SD) age 50.2 (16.9) years, 39% men), 562 461 (96.0%) were euthyroid, 1670 (0.3%) had overt hypothyroidism, 12 087 (2.0%) had subclinical hypothyroidism, 3966 (0.7%) had overt hyperthyroidism, and 6276 (1.0%) had subclinical hyperthyroidism. Compared with the euthyroid individuals, the risk of atrial fibrillation increased with decreasing levels of thyroid stimulating hormone (TSH) from high normal euthyroidism (incidence rate ratio 1.12 (95% CI 1.03 to 1.21)) to subclinical hyperthyroidism with reduced TSH (1.16 (0.99 to 1.36)) and subclinical hyperthyroidism with supressed TSH (1.41 (1.25 to 1.59)). Both overt and subclinical hypothyroidism were associated with a lower risk of atrial fibrillation. Conclusion The risk of atrial fibrillation was closely associated with thyroid activity, with a low risk in overt hypothyroidism, high risk in hyperthyroidism, and a TSH level dependent association with risk of atrial fibrillation across the spectrum of subclinical thyroid disease.

Subclinical and Overt Thyroid Dysfunction and Risk of All-Cause Mortality and Cardiovascular Events: A Large Population Study

CONTEXT Thyroid dysfunction has been associated with both increased all-cause and cardiovascular mortality, but limited data are available on mild thyroid dysfunction and cause-specific mortality. OBJECTIVE The objective of the study was to examine the risk of all-cause mortality, major adverse cardiovascular events (MACEs), and cause-specific events in subjects with overt and subclinical thyroid dysfunction. DESIGN This was a retrospective cohort study. SETTING AND PARTICIPANTS Participants in the study were subjects who underwent thyroid blood tests, without prior thyroid disease, consulting their general practitioner in 2000-2009 in Copenhagen, Denmark. MAIN OUTCOME MEASURE All-cause mortality, MACEs, and cause-specific events identified in nationwide registries were measured. RESULTS A total of 47 327 (8.4%) deaths occurred among 563 700 included subjects [mean age 48.6 (SD ± 18.2) y; 39% males]. All-cause mortality was increased in overt and subclinical hyperthyroidism [age adjusted incidence rates of 16 and 15 per 1000 person-years, respectively; incidence rate ratios (IRRs) 1.25 [95% confidence interval (CI) 1.15-1.36] and 1.23 (95% CI 1.16-1.30)] compared with euthyroid (incidence rate of 12 per 1000 person-years). Risk of MACEs was elevated in overt and subclinical hyperthyroidism [IRRs 1.16 (95% CI 1.05-1.27) and 1.09 (95% CI 1.02-1.16)] driven by heart failure [IRRs 1.14 (95% CI 0.99-1.32) and 1.20 (95% CI 1.10-1.31)]. A reduction of all-cause mortality was observed in subclinical hypothyroidism with TSH of 5-10 mIU/L [IRR 0.92 (95% CI 0.86-0.98)]. CONCLUSIONS Heart failure is the leading cause of an increased cardiovascular mortality in both overt and subclinical hyperthyroidism. Subclinical hypothyroidism with TSH 5-10 mIU/L might be associated with a lower risk of all-cause mortality.

N-terminal-pro-B-type natriuretic peptide (NT-pro-BNP) in different thyroid function states.

objective  N‐terminal B‐type natriuretic peptide (NT‐pro‐BNP) is secreted from the cardiac ventricles in response to volume expansion and pressure overload, and serum levels are elevated in systolic heart failure. The aim of this study was to evaluate the influence of thyroid function on NT‐pro‐BNP.

Hemodynamic Changes After Levothyroxine Treatment in Subclinical Hypothyroidism

In hypothyroidism, lack of thyroid hormones results in reduced cardiac function (cardiac output [CO]), and an increase of systemic vascular resistance (SVR). We speculated whether hemodynamic regulation in subjects with subclinical hypothyroidism (SH) (defined as mildly elevated thyrotropin [TSH] despite free thyroxine [T(4)] and triiodothyronine [T(3)] estimates within reference range) would benefit from levothyroxine (LT(4)) substitution. CO was measured by impedance cardiography, which is an observer independent method with high precision, and mean arterial pressure (MAP) by oscillometry. SVR was then calculated as MAP/CO. Measurements were performed before and after 60 degrees head-up tilting, and before and after LT(4) substitution. Plasma levels of catecholamines were also measured. In 16 otherwise healthy women with SH (ages 44-74 years; serum TSH in mean 17.1 mU/L (range, 6.8-27), and normal free T(4) and T(3) estimates) LT(4) treatment resulted in 6% reduction in supine MAP (p < 0.01), 14% increase in upright CO (p < 0.05), and 13%-20% decrease in SVR (supine and upright position, respectively) (p < 0.05). Plasma norepinephrine as well as epinephrine decreased during LT(4) treatment (p < 0.05). These changes were qualitatively similar but quantitatively less pronounced than in 15 women with overt hypothyroidism, also studied. Taking the two groups together (n = 31), pretreatment thyroid function (expressed as either TSH or free T(4) estimate) correlated to CO and SVR as well as the changes induced by LT(4) (p < 0.05), i.e., the lower the thyroid function the lower the CO and the higher the SVR, and the greater the response to LT(4). We conclude, that LT(4) treatment in SH results in changes in hemodynamic parameters of potentially beneficial character. SH and overt hypothyroidism should be regarded as a continuum, and our data favor earlier and more aggressive treatment of SH.

IGF1 as predictor of all cause mortality and cardiovascular disease in an elderly population.

BACKGROUND IGF1 is believed to influence ageing and development of cardiovascular disease (CVD) through complex mechanisms. Reduced IGF1 levels might be causally associated with conditions accompanying ageing including development of CVD. However, in animal models reduced GH-IGF1 signalling increases lifespan. Reduced IGF1 activity might also be associated with longevity in humans. OBJECTIVE The objective was to investigate if plasma IGF1 levels were associated with all cause mortality, and the development of chronic heart failure (CHF) and a major CV event. PATIENTS AND DESIGN A population based study of 642 individuals, aged 50-89 years. Development of CHF was evaluated in 576 individuals with normal systolic function assessed by echocardiography and without the history of CHF or myocardial infarction. Development of the first major CV event was evaluated in 504 individuals with normal systolic function and without prevalent CVD. Outcomes were ascertained after 5 years using hospital discharge diagnoses. RESULTS Adjustment for risk factors IGF1 values in the fourth quartile versus values below the fourth quartile was associated with increased mortality (n=103), hazard ratio (HR) 1.52 (95% confidence interval (CI) 1.01-2.28; P=0.044). IGF1 in the fourth quartile was also independently associated with risk of development of CHF (n=19), HR 5.02 (95% CI 2.00-12.64; P=0.001) but showed no association with the overall incidence of major CV events (n=58), HR 1.05 (95% CI 0.59-1.90; P=0.861). CONCLUSIONS High IGF1 levels were independently associated with increased all cause mortality and risk of development of CHF, whereas no relation with the overall incidence of CVD was observed.

The appraisal of chronic stress and the development of the metabolic syndrome: a systematic review of prospective cohort studies.

Chronic psychosocial stress has been proposed as a risk factor for the development of the metabolic syndrome (MES). This review gives a systematic overview of prospective cohort studies investigating chronic psychosocial stress as a risk factor for incident MES and the individual elements of MES. Thirty-nine studies were included. An association between chronic psychosocial stress and the development of MES was generally supported. Regarding the four elements of MES: i) weight gain: the prospective studies supported etiological roles for relationship stress, perceived stress, and distress, while the studies on work-related stress (WS) showed conflicting results; ii) dyslipidemi: too few studies on psychosocial stress as a risk factor for dyslipidemia were available to draw a conclusion; however, a trend toward a positive association was present; iii) type 2 diabetes mellitus (DM2): prospective studies supported perceived stress and distress as risk factors for the development of DM2 among men, but not among women, while WS was generally not supported as a risk factor among neither men nor women; iv) hypertension: marital stress and perceived stress might have an influence on blood pressure (BP), while no association was found regarding distress. Evaluating WS the results were equivocal and indicated that different types of WS affected the BP differently between men and women. In conclusion, a longitudinal association between chronic psychosocial stress and the development of MES seems present. However, the number of studies with sufficient quality is limited and the design of the studies is substantially heterogeneous.

Low grade inflammation as measured by levels of YKL-40: Association with an increased overall and cardiovascular mortality rate in an elderly population

BACKGROUND Low grade inflammation is of pathogenic importance in the development of cardiovascular disease (CVD) and type 2 diabetes. The inflammation marker YKL-40 correlates with insulin resistance and is highly expressed in atherosclerotic plaques. We aimed to investigate whether YKL-40 could predict overall and cardiovascular (CV) mortality in a 50+ years population without known CVD. METHODS A representative population sample of 639 individuals aged 50-89 years was recruited from general practices. Examination at baseline included echocardiography and blood and urine samples for CV risk factors and markers including lipids, high sensitive C-reactive protein (hsCRP), N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP) and urinary albumin/creatinine-ratio (UACR). Median follow-up period was 5.0 (0.17-5.28) years. RESULTS In subjects without diabetes and CVD at baseline, increasing YKL-40 levels independently predicted overall and CV mortality rate with hazard ratios of 1.58 (95% confidence interval (CI), 1.12-2.23, p=0.009) and 1.57 (95% CI, 1.00-2.46, p=0.049) after adjustment for age, sex, smoking, total cholesterol, hsCRP, NT-proBNP and UACR. In combined Kaplan-Meier analyses, baseline values of both YKL-40 and UACR above median significantly predicted increased cumulative overall and CV mortality rates in subjects without diabetes or CVD at baseline (30.6% vs. <or=8%, respectively 10.6%<or=3%, p<0.0001). CONCLUSIONS YKL-40 seems to be an independent predictor of overall and CV mortality in an elderly part of the general population without diabetes and CVD. YKL-40 and UACR are both independent predictors, that seem to predict overall and CV mortality in a synergistic way.

Energy availability and the female athlete triad in elite endurance athletes

The female athlete triad (Triad), links low energy availability (EA), with menstrual dysfunction (MD), and impaired bone health. The aims of this study were to examine associations between EA/MD and energy metabolism and the prevalence of Triad‐associated conditions in endurance athletes. Forty women [26.2 ± 5.5 years, body mass index (BMI) 20.6 ± 2.0 kg/m2, body fat 20.0 ± 3.0%], exercising 11.4 ± 4.5 h/week, were recruited from national teams and competitive clubs. Protocol included gynecological examination; assessment of bone health; indirect respiratory calorimetry; diet and exercise measured 7 days to assess EA; eating disorder (ED) examination; blood analysis. Subjects with low/reduced EA (< 45 kcal/kg FFM/day), had lower resting metabolic rate (RMR) compared with those with optimal EA [28.4 ± 2.0 kcal/kg fat‐free mass (FFM)/day vs 30.5 ± 2.2 kcal/kg FFM/day, P < 0.01], as did subjects with MD compared with eumenorrheic subjects (28.6 ± 2.4 kcal/kg FFM/day vs 30.2 ± 1.8 kcal/kg FFM/day, P < 0.05). 63% had low/reduced EA, 25% ED, 60% MD, 45% impaired bone health, and 23% had all three Triad conditions. 53% had low RMR, 25% hypercholesterolemia, and 38% hypoglycemia. Conclusively, athletes with low/reduced EA and/or MD had lowered RMR. Triad‐associated conditions were common in this group of athletes, despite a normal BMI range. The high prevalence of ED, MD, and impaired bone health emphasizes the importance of prevention, early detection, and treatment of energy deficiency.

The LEAF questionnaire: a screening tool for the identification of female athletes at risk for the female athlete triad.

Background Low energy availability (EA) in female athletes with or without an eating disorder (ED) increases the risk of oligomenorrhoea/functional hypothalamic amenorrhoea and impaired bone health, a syndrome called the female athlete triad (Triad). There are validated psychometric instruments developed to detect disordered eating behaviour (DE), but no validated screening tool to detect persistent low EA and Triad conditions, with or without DE/ED, is available. Aim The aim of this observational study was to develop and test a screening tool designed to identify female athletes at risk for the Triad. Methods Female athletes (n=84) with 18–39 years of age and training ≥5 times/week filled out the Low Energy Availability in Females Questionnaire (LEAF-Q), which comprised questions regarding injuries and gastrointestinal and reproductive function. Reliability and internal consistency were evaluated in a subsample of female dancers and endurance athletes (n=37). Discriminant as well as concurrent validity was evaluated by testing self-reported data against measured current EA, menstrual function and bone health in endurance athletes from sports such as long distance running and triathlon (n=45). Results The 25-item LEAF-Q produced an acceptable sensitivity (78%) and specificity (90%) in order to correctly classify current EA and/or reproductive function and/or bone health. Conclusions The LEAF-Q is brief and easy to administer, and relevant as a complement to existing validated DE screening instruments, when screening female athletes at risk for the Triad, in order to enable early detection and intervention.