Due to the burden of coronary heart disease (CHD), the monitoring of CHD trends is required. This study sought to examine the acute myocardial infarction (AMI) trends in attack and mortality rates, ...and in 28-day case-fatality, in six European populations during 1985-2010.
Data consisted of 78 128 AMI events included in eight population-based registries from Finland (several populations), Italy (Brianza and Varese), Germany (Augsburg), France (Haute-Garonne), Spain (Girona) and Estonia (Tallinn). AMI event rates and case-fatality trends were analysed using the annual percentage change (APC) obtained by negative binomial and joinpoint regression.
AMI attack and mortality rates decreased in most populations. Finland experienced the steepest decline in attack rates (APC=-4.4% (95% CI -5.1 to -2.9) in men; -4.0% (-5.1 to -2.8), in women). Total-hospital and inhospital case-fatality decreased in all populations except in Tallinn. The steepest decline in total case-fatality occurred in Spain (-3.8% (-5.3 to -2.4) in men; -5.1% (-6.9 to -3.3) in women). Prehospital case-fatality trends differed significantly by population and sex. The trends for all included populations showed a significant decline in AMI event rates and case-fatality, in both sexes and all age groups. However, in women aged 65-74 years, a significant increase in total case-fatality occurred in 2005-2010 (4.7% (0.7 to 8.8)).
AMI event rates and inhospital case-fatality declined in 1985-2010 in almost all populations analysed. Prehospital case-fatality declined only in certain population groups, showing differences by sex. These results highlight the need of specific strategies in AMI prevention for certain groups and populations.
Recent studies focused on modulating factors of paraoxonase-1 (PON1) activity. In some studies the association between pro-inflammatory markers and PON1 activity was examined, but so far no ...population-based investigations on this issue have been conducted. The present study investigated the relationships between the pro-inflammatory markers tumor necrosis factor (TNF)-α, leptin, interleukin (IL)-6, and high-sensitive C-reactive protein (hs-CRP) and paraoxonase and arylesterase, two hydrolytic activities of PON1, in the population-based Bavarian Food Consumption Survey II.
Based on 504 participants (217 men, 287 women), the relationship between the pro-inflammatory markers and the outcomes paraoxonase and arylesterase activities were investigated using multivariable linear models.
Circulating plasma levels of leptin (P-value < 0.0001), hs-CRP (P-value = 0.031) and IL-6 (P-value = 0.045) were significantly non-linearly associated with arylesterase activity. Leptin levels were also significantly associated with paraoxonase activity (P-value = 0.024) independently from confounding factors, including high-density lipoprotein (HDL) cholesterol. With increasing levels of these inflammatory parameters, arylesterase and paraoxonase activities increased; however, at higher levels (> 75th percentile) the activities reached a plateau or even decreased somewhat. After Bonferroni-Holm correction, only leptin remained non-linearly but significantly associated with arylesterase activity (adjusted overall P-value < 0.0001). Neither age nor sex nor obesity modified the associations. No association was found between TNF-α and paraoxonase or arylesterase activity.
The present findings suggest that in persons with very high levels of inflammation, PON1 activity may be impaired, a fact that might subsequently be accompanied by a higher risk for cardiometabolic diseases. Whether or not the measurement of PON1 activity in combination with a lipid profile and certain inflammatory markers could improve the prediction of cardiometabolic diseases in middle-aged individuals from the general population should be evaluated in clinical studies.
BackgroundBased on Barker’s hypothesis, some studies investigated the associations between birth weight and several disorders. Apart from issues with statistical power and well-known shortcomings of ...the observational study design, there are no studies accounting for changes in weight-related body size over the life course regarding rheumatoid arthritis, psoriasis, psoriatic arthritis and multiple sclerosis.MethodsUsing genetic information of up to 806 834 participants, this study investigated the associations between time-varying weight-related body size from birth to adulthood and the mentioned autoimmune diseases. Performing Mendelian randomisation (MR), the radial inverse-variance weighted approach was used iteratively in primary analyses. Robustness of the results was confirmed in several sensitivity analyses. Potential time-dependent mediation mechanisms were identified through network-clustering and assessed using multivariable MR.ResultsGenetically predicted birth weight (fetal effect) was positively associated with rheumatoid arthritis (OR 1.44; 95% CI 1.17 to 1.77; Padj =0.005) but not with psoriasis, psoriatic arthritis or multiple sclerosis. This association was found to be mediated by body mass index (BMI) in adulthood (OR 1.45; 95% CI 1.14 to 1.84; Padj =0.019) rather than childhood. The direct effect of birth weight attenuated (OR 1.19; 95% CI 0.88 to 1.62); Padj =1) after adjustment for time-varying BMI.ConclusionIncreased birth weight appears to be a risk factor for later manifestation of rheumatoid arthritis due to both fetal genetic components and high BMI persisting into adulthood. Approaches to prevent and minimise the risk of rheumatoid arthritis could include preventing obesity in adults with high birth weight.
BackgroundAttention-deficit/hyperactivity disorder (ADHD) is a lifespan neurodevelopmental condition resulting from complex interactions between genetic and environmental risk factors. There is ...evidence that ADHD is associated with other mental disorders, but it remains unclear whether and in what way a causal relationship exists.ObjectiveTo investigate the direct and indirect causal paths between ADHD and seven common mental disorders.MethodsTwo-sample network Mendelian randomisation analysis was performed to identify psychiatric disorders causally related to ADHD. Total and direct effects were estimated in an univariable and multivariable setting, respectively. Robustness of results was ensured in three ways: a range of pleiotropy-robust methods, an iterative approach identifying and excluding outliers, and use of up to two genome-wide association studies per outcome to replicate results and calculate subsequently pooled meta-estimates.ResultsGenetic liability to ADHD was independently associated with the risk of anorexia nervosa (OR 1.28 (95% CI 1.11 to 1.47); p=0.001). A bidirectional association was found with major depressive disorder (OR 1.09 (95% CI 1.03 to 1.15); p=0.003 in the forward direction and OR 1.76 (95% CI 1.50 to 2.06); p=4×10−12 in the reverse direction). Moreover, after adjustment for major depression disorder, a direct association with both suicide attempt (OR 1.30 (95% CI 1.16 to 1.547); p=2×10−5) and post-traumatic stress disorder (OR 1.18 (95% CI 1.05 to 1.33); p=0.007) was observed. There was no evidence of a relationship with anxiety, bipolar disorder or schizophrenia.ConclusionsThis study suggests that ADHD is an independent risk factor for a number of common psychiatric disorders.Clinical implicationsThe risk of comorbid psychiatric disorders in individuals with ADHD needs to be considered both in diagnosis and treatment.
Shock index (SI) and modified shock index (mSI) are useful instruments for early risk stratification in acute myocardial infarction (AMI) patients. They are strong predictors for short-term ...mortality. Nevertheless, the association between SI or mSI and long-term mortality in AMI patients has not yet been sufficiently examined.
For this study, a total of 10,174 patients with AMI was included. All cases were prospectively recorded by the population-based Augsburg Myocardial Infarction Registry from 2000 until 2017. Endpoint was all-cause mortality with a median observational time of 6.5 years IQR: 3.5-7.4. Using ROC analysis and calculating Youden-Index, the sample was dichotomized into a low and a high SI and mSI group, respectively. Moreover, multivariable adjusted COX regression models were calculated. All analyses were performed for the total sample as well as for STEMI and NSTEMI cases separately.
Optimal cut-off values were 0.580 for SI and 0.852 for mSI (total sample). AUC values were 0.6382 (95% CI: 0.6223-0.6549) for SI and 0.6552 (95% CI: 0.6397-0.6713) for mSI. Fully adjusted COX regression models revealed significantly higher long-term mortality for patients with high SI and high mSI compared to patients with low indices (high SI HR: 1.42 1.32-1.52, high mSI HR: 1.46 1.36-1.57). Furthermore, the predictive ability was slightly better for mSI compared to SI and more reliable in NSTEMI cases compared to STEMI cases (for SI and mSI).
High SI and mSI are useful tools for early risk stratification including long-term outcome especially in NSTEMI cases, which can help physicians to make decision on therapy. NSTEMI patients with high SI and mSI might especially benefit from immediate invasive therapy.
Key messages
Shock index and modified shock index are predictors of long-term mortality after acute myocardial infarction.
Both indices predict long-term mortality not only for STEMI cases, but even more so for NSTEMI cases.
Analyzing epidemiological data with simplified mathematical models of disease development provides a link between the time‐course of incidence and the underlying biological processes. Here we point ...out that considerable modeling flexibility is gained if the model is solved by simulation only. To this aim, a model of atherosclerosis is proposed: a Markov Chain with continuous state space which represents the coronary artery intimal surface area involved with atherosclerotic lesions of increasing severity. Myocardial infarction rates are assumed to be proportional to the area of most severe lesions. The model can be fitted simultaneously to infarction incidence rates observed in the KORA registry, and to the age‐dependent prevalence and extent of atherosclerotic lesions in the PDAY study. Moreover, the simulation approach allows for non‐linear transition rates, and to consider at the same time randomness and inter‐individual heterogeneity. Interestingly, the fit revealed significant age dependence of parameters in females around the age of menopause, qualitatively reproducing the known vascular effects of female sex hormones. For males, the incidence curve flattens for higher ages. According to the model, frailty explains this flattening only partially, and saturation of the disease process plays also an important role. This study shows the feasibility of simulating subclinical and epidemiological data with the same mathematical model. The approach is very general and may be extended to investigate the effects of risk factors or interventions. Moreover, it offers an interface to integrate quantitative individual health data as assessed, for example, by imaging.
As promising compounds to lower Lipoprotein(a) (Lp(a)) are emerging, the need for a precise characterization and comparability of the Lp(a)-associated cardiovascular risk is increasing. Therefore, we ...aimed to evaluate the distribution of Lp(a) concentrations across the European population, to characterize the association with cardiovascular outcomes and to provide high comparability of the Lp(a)-associated cardiovascular risk by use of centrally determined Lp(a) concentrations.
Based on the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE)-project, we analysed data of 56 804 participants from 7 prospective population-based cohorts across Europe with a maximum follow-up of 24 years. All Lp(a) measurements were performed in the central BiomarCaRE laboratory (Biokit Quantia Lp(a)-Test; Abbott Diagnostics). The three endpoints considered were incident major coronary events (MCE), incident cardiovascular disease (CVD) events, and total mortality. We found lower Lp(a) levels in Northern European cohorts (median 4.9 mg/dL) compared to central (median 7.9 mg/dL) and Southern European cohorts (10.9 mg/dL) (Jonckheere-Terpstra test P < 0.001). Kaplan-Meier curves showed the highest event rate of MCE and CVD events for Lp(a) levels ≥90th percentile (log-rank test: P < 0.001 for MCE and CVD). Cox regression models adjusted for age, sex, and cardiovascular risk factors revealed a significant association of Lp(a) levels with MCE and CVD with a hazard ratio (HR) of 1.30 for MCE 95% confidence interval (CI) 1.15‒1.46 and of 1.25 for CVD (95% CI 1.12‒1.39) for Lp(a) levels in the 67‒89th percentile and a HR of 1.49 for MCE (95% CI 1.29‒1.73) and of 1.44 for CVD (95% CI 1.25‒1.65) for Lp(a) levels ≥ 90th percentile vs. Lp(a) levels in the lowest third (P < 0.001 for all). There was no significant association between Lp(a) levels and total mortality. Subgroup analysis for a continuous version of cube root transformed Lp(a) identified the highest Lp(a)-associated risk in individuals with diabetes HR for MCE 1.31 (95% CI 1.15‒1.50) and for CVD 1.22 (95% CI 1.08‒1.38) compared to those without diabetes HR for MCE 1.15 (95% CI 1.08‒1.21; HR for CVD 1.13 (1.07-1.19) while no difference of the Lp(a)- associated risk were seen for other cardiovascular high risk states. The addition of Lp(a) levels to a prognostic model for MCE and CVD revealed only a marginal but significant C-index discrimination measure increase (0.001 for MCE and CVD; P < 0.05) and net reclassification improvement (0.010 for MCE and 0.011 for CVD).
In this large dataset on harmonized Lp(a) determination, we observed regional differences within the European population. Elevated Lp(a) was robustly associated with an increased risk for MCE and CVD in particular among individuals with diabetes. These results may lead to better identification of target populations who might benefit from future Lp(a)-lowering therapies.
Aims/hypothesis
Cardiac autonomic nervous dysfunction (CAND) raises the risk of mortality, but the glycaemic threshold at which it develops is unclear. We aimed to determine the prevalence of, risk ...factors for and impact of CAND in glucose intolerance and diabetes.
Methods
Among 1,332 eligible participants aged 55–74 years in the population-based cross-sectional KORA S4 study, 130 had known diabetes mellitus (k-DM), and the remaining 1,202 underwent an OGTT. Heart rate variability (HRV) and QT variability were computed from supine 5 min ECGs.
Results
In all, 565 individuals had normal glucose tolerance (NGT), 336 had isolated impaired fasting glucose (i-IFG), 72 had isolated impaired glucose tolerance (i-IGT), 151 had combined IFG–IGT (IFG–IGT) and 78 had newly detected diabetes mellitus (n-DM). Adjusted normal HRV limits were defined in the NGT population (5th and 95th percentiles). Three HRV measures were more frequently abnormal in those with k-DM, n-DM, IFG–IGT and i-IFG than in those with NGT (
p <
0.05). The rates of CAND (≥2 of 4 HRV indices abnormal) were: NGT, 4.5%; i-IFG, 8.1%; i-IGT, 5.9%; IFG–IGT, 11.4%; n-DM, 11.7%; and k-DM, 17.5% (
p <
0.05 vs NGT, except for i-IGT). Reduced HRV was associated with cardiovascular risk factors used to construct a simple screening score for CAND. Mortality was higher in participants with reduced HRV (
p <
0.05 vs normal HRV).
Conclusions/interpretation
In the general population aged 55–74 years, the prevalence of CAND is increased not only in individuals with diabetes, but also in those with IFG–IGT and, to a lesser degree, in those with i-IFG. It is associated with mortality and modifiable cardiovascular risk factors which may be used to screen for diminished HRV in clinical practice.
C-reactive protein (CRP), an exquisitely sensitive systemic marker of inflammation, has emerged as an independent predictor of cardiovascular diseases (CVD). Because other chronic diseases are also ...associated with an inflammatory response, we sought to assess the association of high-sensitivity CRP (hsCRP) with total and cause-specific mortality in a large cohort of middle-aged men.
We measured hsCRP at baseline in 3620 middle-aged men, randomly drawn from 3 samples of the general population in the Augsburg area (Southern 0Germany) in 1984-85, 1989-90, and 1994-95. Outcome was defined as all deaths, fatal CVD, fatal coronary heart disease (CHD) including sudden cardiac deaths, and cancer deaths.
During an average follow-up of 7.1 years, 408 deaths occurred (CVD 196, CHD 129, cancer 127). In multivariable Cox regression analysis, subjects with hsCRP >3 mg/L at baseline showed an almost 2-fold increased risk to die vs those with hsCRP <1 mg/L hazard ratio (HR) 1.88, 95% CI 1.41-2.52. HRs were 2.15 (95% CI 1.39-3.34) for fatal CVD, 1.74 (1.04-2.92) for fatal CHD, and 1.65 (1.01-2.68) for cancer mortality. In contrast, neither total nor HDL cholesterol significantly predicted all-cause or cancer mortality, and cholesterol had only modest effects on CVD mortality.
Our results suggest that increased circulating hsCRP concentrations are associated with an increased risk of death from several widespread chronic diseases. Persistently increased hsCRP is a sensitive and valuable nonspecific indicator of an ongoing disease process that deserves serious and careful medical attention.
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