Till Ittermann

Cohort Profile: The Study of Health in Pomerania

Henry Volzke, y Dietrich Alte,1y Carsten Oliver Schmidt, Dorte Radke, Roberto Lorbeer, Nele Friedrich, Nicole Aumann, Katharina Lau, Michael Piontek, Gabriele Born, Christoph Havemann, Till Ittermann, Sabine Schipf, Robin Haring, Sebastian E Baumeister, Henri Wallaschofski, Matthias Nauck, Stephanie Frick, Andreas Arnold, Michael Junger, Julia Mayerle, Matthias Kraft, Markus M Lerch, Marcus Dorr, Thorsten Reffelmann, Klaus Empen, Stephan B Felix, Anne Obst, Beate Koch, Sven Glaser, Ralf Ewert, Ingo Fietze, Thomas Penzel, Martina Doren, Wolfgang Rathmann, Johannes Haerting, Mario Hannemann, Jurgen Ropcke, Ulf Schminke, Clemens Jurgens, Frank Tost, Rainer Rettig, Jan A Kors, Saskia Ungerer, Katrin Hegenscheid, Jens-Peter Kuhn, Julia Kuhn, Norbert Hosten, Ralf Puls, Jorg Henke, Oliver Gloger, Alexander Teumer, Georg Homuth, Uwe Volker, Christian Schwahn, Birte Holtfreter, Ines Polzer, Thomas Kohlmann, Hans J Grabe, Dieter Rosskopf, Heyo K Kroemer, Thomas Kocher, Reiner Biffar,17,y Ulrich John20y and Wolfgang Hoffmann1y

Platelet factor 4 binds to bacteria-inducing antibodies cross-reacting with the major antigen in heparin-induced thrombocytopenia

A clinically important adverse drug reaction, heparin-induced thrombocytopenia (HIT), is induced by antibodies specific for complexes of the chemokine platelet factor 4 (PF4) and the polyanion heparin. Even heparin-naive patients can generate anti-PF4/heparin IgG as early as day 4 of heparin treatment, suggesting preimmunization by antigens mimicking PF4/heparin complexes. These antibodies probably result from bacterial infections, as (1) PF4 bound charge-dependently to various bacteria, (2) human heparin-induced anti-PF4/heparin antibodies cross-reacted with PF4-coated Staphylococcus aureus and Escherichia coli, and (3) mice developed anti-PF4/heparin antibodies during polymicrobial sepsis without heparin application. Thus, after binding to bacteria, the endogenous protein PF4 induces antibodies with specificity for PF4/polyanion complexes. These can target a large variety of PF4-coated bacteria and enhance bacterial phagocytosis in vitro. The same antigenic epitopes are expressed when pharmacologic heparin binds to platelets augmenting formation of PF4 complexes. Boosting of preformed B cells by PF4/heparin complexes could explain the early occurrence of IgG antibodies in HIT. We also found a continuous, rather than dichotomous, distribution of anti-PF4/heparin IgM and IgG serum concentrations in a cross-sectional population study (n = 4029), indicating frequent preimmunization to modified PF4. PF4 may have a role in bacterial defense, and HIT is probably a misdirected antibacterial host defense mechanism.

Early‐onset and persisting thrombocytopenia in post‐cardiac surgery patients is rarely due to heparin‐induced thrombocytopenia, even when antibody tests are positive

See also Gruel Y, Pouplard C. Post‐operative platelet count profile: the most reliable tool for identifying patients with true heparin‐induced thrombocypenia after cardiac surgery. This issue, pp 27–29.

Reference values for cardiopulmonary exercise testing in healthy volunteers: the SHIP study

Cardiopulmonary exercise testing (CPET) is a widely applied clinical procedure. The aim of the present study was to acquire a comprehensive set of reference values for cardiopulmonary responses to exercise and to evaluate possible associations with sex, age and body mass index (BMI). A standardised progressive incremental exercise protocol on a cycle ergometer was applied to 1,708 volunteers of a cross-sectional epidemiologic survey, called “Study of Health in Pomerania”. Individuals with cardiopulmonary disorders, or echocardiographic or lung function pathologies, were excluded. The influence of potential confounding factors, such as smoking, taking β-blockers, hypertension, diastolic dysfunction, BMI and physical activity, were analysed for their influencing power. Reference values of CPET parameters were determined by regression analyses. Of the volunteers, 542 current smokers and obese individuals were excluded for not being representative of a healthy population. The final sample size was 534 (253 males), with age 25–80 yrs. The current study provides a representative set of reference values for CPET parameters based on age and weight. Sex and age have a significant influence on exercise parameters. While addressing the problem of a selection bias, the current study provides the first comprehensive set of reference values obtained in a large number of healthy volunteers within a population-based survey.

Low serum magnesium concentrations predict cardiovascular and all-cause mortality

BACKGROUND Low serum magnesium (Mg(++)) levels are associated with future development of left ventricular hypertrophy independently of common cardiovascular risk factors, as recently demonstrated in the five-year follow-up of the population-based Study of Health in Pomerania (SHIP). As left ventricular hypertrophy has significant prognostic implications, we hypothesized that serum Mg(++) levels are associated with cardiovascular mortality. METHOD AND RESULTS All-cause mortality and cardiovascular mortality were analyzed in relationship to serum Mg(++) concentrations at baseline by Cox proportional hazard model in SHIP (n=4203, exclusion of subjects with Mg(++) supplementation). The median duration of mortality follow-up was 10.1 years (25th percentile: 9.4 years, 75th percentile: 10.8 years; 38,075 person-years). During the follow-up, 417 deaths occurred. Mortality in subjects with Mg(++)≤0.73 mmol/l was significantly higher for all-cause deaths (10.95 death per 1000 person years), and cardiovascular deaths (3.44 deaths per 1000 person years) in comparison to higher Mg(++) concentrations (1.45 deaths from all-cause per 1000 person years, 1.53 deaths from cardiovascular cause per 1000 person years). This association remained statistically significant after adjustment for multiple cardiovascular risk factors, including arterial hypertension, and antihypertensive therapy including diuretics (log-rank-test p=0.0001 for all-cause mortality, and p=0.0174 for cardiovascular mortality). CONCLUSIONS Low serum Mg(++) levels are associated with higher all-cause mortality and cardiovascular mortality. This corresponds well with recent findings that hypomagnesemia is associated with the increase of left ventricular mass over the following years.

Prevalence, incidence and risk factors of testosterone deficiency in a population-based cohort of men: results from the study of health in Pomerania

Objective. Low total testosterone levels (TT) have been associated with increased morbidity and mortality. However, the prevalence and incidence of testosterone deficiency (TD) in association with its risk has not been assessed systematically to date. Methods. Data from the prospective population-based Study of Health in Pomerania were used. From the 2117 men aged 20–79 years at baseline, 1490 men with complete TT data were analysed. Crude and age-specific prevalence and incidence rates of TD were estimated by TT levels below the age-specific 10th percentile. Analysis of covariance and Poisson regression models were used to assess the association of socio-demographic characteristics, health-related lifestyle, as well as somatometric, medical and laboratory measures with risk of incident TD. Results. TD baseline prevalence was 10.4% (N = 155) and incidence 11.7 per 1000 person-years. TT levels showed a significant age-related decline with an unadjusted rate of 0.05 nmol/l per year. Obesity, metabolic syndrome, diabetes and dyslipidaemia were identified as risk factors of incident TD. Subpopulations of men without the revealed risk factors at both examinations maintained constant TT levels over time. Conclusions. Besides aging alone, lifestyle and different comorbidities were associated with TT level decline, suggesting that the age-related TT decline may be at least partly prevented through the management of potentially modifiable risk factors and health related behaviour.

Heparin-induced thrombocytopenia: towards standardization of platelet factor 4/heparin antigen tests

Summary.  Background: Laboratory confirmation of heparin‐induced thrombocytopenia (HIT) is based on detection of heparin‐dependent platelet‐activating antibodies. Platelet factor 4 (PF4)/heparin enzyme‐immunoassays (EIA) are a widely available surrogate for platelet‐activating antibodies. Objective: Defining the optical density (OD) reactivity profiles of a PF4/heparin EIA in reference subject and patient populations and the correlation of the EIA results (expressed in OD units) with the prevalence of platelet‐activating antibodies. Patients/methods: Using quantile regression we determined the 97.5th percentile of PF4/heparin‐immunoglobulin G (IgG) EIA reactivities in non‐heparin‐treated individuals [blood donors (n = 935)] and patients before heparin therapy (n = 1207). In patients with suspected HIT, we compared the correlation of EIA‐IgG reactivities (Greifswald laboratory; n = 2821) and the heparin‐induced platelet activation assay (HIPA) with the correlation of reactivities of another EIA‐IgG (McMaster laboratory; n = 1956) with the serotonin‐release assay (SRA). Results: PF4/heparin‐IgG EIA OD reactivities had a lower OD 97.5th percentile in blood donors compared with patient groups before heparin treatment (P < 0.001). The percentage of sera testing positive in the functional assays strongly correlated with PF4/heparin‐IgG EIA OD reactivities in both laboratories with very similar results (correlation coefficient > 0.9) when normalized OD ranges (maximum OD divided by 10) were used instead of absolute OD values. Conclusions: Results of PF4/heparin‐IgG EIA should not be reported as only positive or negative as there is no single acceptable cut‐off value. Instead, reporting PF4/heparin‐IgG EIA OD results in ranges allows for risk‐stratified prediction for presence of platelet‐activating antibodies. Use of normalized OD ranges permits a standardized approach for inter‐laboratory comparisons.

Association of natural anti-platelet factor 4/heparin antibodies with periodontal disease

Platelet factor 4 (PF4) and heparin (H) form PF4/H complexes, the target of the immune reaction in heparin-induced thrombocytopenia (HIT). HIT seems to be a secondary immune response as anti-PF4/H-IgG antibodies occur as early as day 4 of heparin treatment. This study investigated whether prevalent infections such as periodontitis may induce the PF4/H immune response as: (1) natural anti-PF4/H Abs are present in the normal population; (2) PF4 bound to bacteria exposes the same antigen(s) as PF4/H complexes; and (3) sepsis induces PF4/H Abs in mice. We found PF4 bound to periodontal pathogens (Aggregatibacter actinomycetemcomitans; Porphyromonas gingivalis) enabling subsequent binding of human anti-PF4/H Abs. The association of natural PF4/H Abs and periodontitis was assessed in a case-control study, enrolling individuals with natural anti-PF4/H Abs (n = 40 matched pairs), and in the cross-sectional population-based Study of Health in Pomerania (SHIP; n = 3500). Both studies showed a robust association between periodontitis and presence of anti-PF4/H Abs independent of inflammation markers (case-control study: lowest vs highest tertile, odds ratio, 7.12 [95% confidence interval, 1.73-46.13; P = .005]; SHIP study, p(trend) ≤ 0.001). Thus, preimmunization to PF4/bacteria complexes by prevalent infections, for example, periodontitis, likely explains the presence of natural anti-PF4/heparin Abs and the early occurrence of anti-PF4/H-IgG in HIT.

Decreased serum TSH levels are not associated with mortality in the adult northeast German population

OBJECTIVE Results of cohort studies on the association between decreased serum TSH levels and mortality are conflicting. Some studies demonstrated an increased mortality risk in subjects with decreased serum TSH levels, others did not. Even meta-analyses revealed contradictory results. We undertook the present study to investigate the association between decreased serum TSH levels and mortality in the large population-based Study of Health in Pomerania (SHIP). DESIGN AND METHODS Data from 3651 individuals from SHIP without known thyroid disorders or thyroid treatment were analyzed. Serum TSH, free triiodothyronine, and free thyroxine levels were determined by immunochemiluminescent procedures. Decreased TSH was defined as serum TSH levels below 0.25 mIU/l. Cox regression was used to associate decreased TSH levels with mortality. RESULTS The median duration of follow-up was 8.5 years (30 126 person years). During follow-up, 299 individuals (6.9%) died corresponding to a death rate of 9.92 deaths per 1000 person years. Survival time was shorter in subjects with decreased serum TSH levels compared to euthyroid individuals. After adjustment for age and sex, however, there was no association between decreased serum TSH levels and all-cause mortality (hazard ratio: 0.95; 95% confidence interval: 0.67; 1.36). Likewise, decreased serum TSH levels were neither associated with cardiovascular nor with cancer mortality. CONCLUSIONS There is no independent association of decreased serum TSH levels with all-cause, cardiovascular, and cancer mortality in the adult northeast German population. Although our study has some strengths, we cannot finally conclude on therapeutical implications in individuals with subclinical thyroid diseases.

Quantitative chemical shift-encoded MRI is an accurate method to quantify hepatic steatosis.

To compare the accuracy of liver fat quantification using a three‐echo chemical shift‐encoded magnetic resonance imaging (MRI) technique without and with correction for confounders with spectroscopy (MRS) as the reference standard.