Regional differences of macrovascular disease in Northeast and South Germany: the population-based SHIP-TREND and KORA-F4 studies

Abstract Background Previous studies found regional differences in the prevalence and incidence of type 2 diabetes between Northeast and South of Germany. The aim of this study was to investigate if regional variations are also present for macrovascular disease in people with type 2 diabetes and in the general population. A further aim was to investigate if traditional risk factors of macrovascular complications can explain these regional variations. Methods Data of persons aged 30–79 from two regional population-based studies, SHIP-TREND (Northeast Germany, 2008–2012, n = 2539) and KORA-F4 (South Germany, 2006–2008, n = 2932), were analysed. Macrovascular disease was defined by self-reported previous myocardial infarction, stroke or coronary angiography. Multivariable logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI) for prevalence of macrovascular disease in persons with type 2 diabetes and in the general population. Results The prevalence of macrovascular disease in persons with type 2 diabetes and in the general population was considerably higher in the Northeast (SHIP-TREND: 32.8 and 12.0%) than in the South of Germany (KORA-F4: 24.9 and 8.8%), respectively. The odds of macrovascular disease in persons with type 2 diabetes was 1.66 (95% CI: 1.11–2.49) in the Northeast in comparison to the South after adjustment for sex, age, body mass index, hypertension, hyperlipidemia and smoking. In the general population, SHIP-TREND participants also had a significantly increased odds of macrovascular disease compared to KORA-F4 participants (OR = 1.63, 95% CI: 1.33–2.00). After excluding coronary angiography (myocardial infarction or stroke only), the ORs for region decreased in all models, but the difference between SHIP-TREND and KORA-F4 participants was still significant in the age- and sex-adjusted model for the general population (OR = 1.34, 95% CI: 1.01–1.78). Conclusions This study provides an indication for regional differences in macrovascular disease, which is not explained by traditional risk factors. Further examinations of other risk factors, such as regional deprivation or geographical variations in medical care services are needed

Estudo Vida e Saúde em Pomerode (SHIP-Brazil): objetivos, aspectos metodológicos e resultados descritivos

Background Few studies compared populations with similar genetic and culture background on different continents with standardized methods. Objective To describe methodological issues of the Study of Health in Pomerode - SHIP-Brazil and some characteristics of the participants of the baseline examination. Design and Setting Prospective, population-based cohort study of a representative sample of residents (aged 20 to 79 years) of Pomerode, Santa Catarina, Brazil. Methods Data for the baseline survey (from 2014 to 2018) were collected through interviews and medical examinations, including socio-demographic and lifestyle information, clinical and subclinical conditions, oral and mental health, among others. Biosamples (blood, urine, stool, and saliva) were collected and stored. Methods of data collection and quality control are described. Preliminary descriptive statistics were performed. Results The response rate was 67.6% (n=2,488 individuals). The Kappa test-retest of some variables varied from 0.54 to 1.0. German culture participants are older (46.5 vs 38.7 years), self-declared white (97.3% vs 82.1%), more frequently never smokers (71.4% vs 66.9%) but had higher risk of consuming alcohol (16.9% vs 13.4%) compared to participants with non-German background. Germans were taller (169 cm vs 166 cm), had greater abdominal circumference among men (101.9 cm vs 97.3 cm). Furthermore, they reported more multimorbidity (56.7% vs 43.6%) , had more arterial hypertension (30.7% vs 18.5%), but less depression (15.4% vs 19,1%) than non-Germans. Conclusions The interaction of genetic and social/environmental issues should be examined to understand the role of risk factors on clinical conditions observed.Introdução Poucos estudos compararam populações com histórico genético e cultural semelhante em diferentes continentes com métodos padronizados. Objetivos Descrever questões metodológicas do estudo de “Vida e Saúde em Pomerode - SHIP-Brazil” e algumas características dos participantes do exame inicial do estudo. Desenho de estudo e local Estudo de coorte prospectivo de base populacional em amostra representativa de moradores (20 a 79 anos) de Pomerode, Santa Catarina. Métodos As informações para a linha de base (de 2014 a 2018) foram coletadas por meio de entrevistas e exames médicos, incluindo dados sociodemográficos, de estilo de vida, condições clínicas e subclínicas, saúde bucal e mental, entre outros. Amostras biológicas (sangue, urina, fezes e saliva) foram coletadas e armazenadas. A coleta de dados e o controle de qualidade foram descritos. Foram realizadas análises descritivas preliminares. Resultados A taxa de resposta foi de 67,6% (n=2.488 indivíduos). O Kappa teste-reteste de algumas variáveis variou  de 0,54 a 1,0. Os participantes de cultura alemã são mais velhos (46,5 vs 38,7 anos ), autodeclarados brancos (97,3% vs 82,1%), com menor número de fumantes (71,4% vs 66,9%), mas tiveram maior risco de consumir álcool (16,9% vs 13,4%), eram mais altos (169 cm vs 166 cm), tinham maior circunferência abdominal entre os homens (101,9 cm vs 97,3 cm) em comparação com participantes “não-alemães”. Pessoas de cultura alemã relataram mais multimorbidade (56,7% vs 43,6%), apresentavam mais hipertensão arterial (30,7% vs 18,5%), mas menos depressão (15,4% vs 19,1%). Conclusões A interação genética e social/ambiental devem ser examinadas para melhor entender o papel desses fatores de risco nas condições clínicas observadas

Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies

BACKGROUND: Genetic determinants of stroke, the leading neurological cause of death and disability, are poorly understood and have seldom been explored in the general population. Our aim was to identify additional loci for stroke by doing a meta-analysis of genome-wide association studies. METHODS: For the discovery sample, we did a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts comprising 84 961 participants, of whom 4348 had stroke. Stroke diagnosis was ascertained and validated by the study investigators. Mean age at stroke ranged from 45·8 years to 76·4 years, and data collection in the studies took place between 1948 and 2013. We did validation analyses for variants yielding a significant association (at p<5 × 10(-6)) with all-stroke, ischaemic stroke, cardioembolic ischaemic stroke, or non-cardioembolic ischaemic stroke in the largest available cross-sectional studies (70 804 participants, of whom 19 816 had stroke). Summary-level results of discovery and follow-up stages were combined using inverse-variance weighted fixed-effects meta-analysis, and in-silico lookups were done in stroke subtypes. For genome-wide significant findings (at p<5 × 10(-8)), we explored associations with additional cerebrovascular phenotypes and did functional experiments using conditional (inducible) deletion of the probable causal gene in mice. We also studied the expression of orthologs of this probable causal gene and its effects on cerebral vasculature in zebrafish mutants. FINDINGS: We replicated seven of eight known loci associated with risk for ischaemic stroke, and identified a novel locus at chromosome 6p25 (rs12204590, near FOXF2) associated with risk of all-stroke (odds ratio [OR] 1·08, 95% CI 1·05-1·12, p=1·48 × 10(-8); minor allele frequency 21%). The rs12204590 stroke risk allele was also associated with increased MRI-defined burden of white matter hyperintensity-a marker of cerebral small vessel disease-in stroke-free adults (n=21 079; p=0·0025). Consistently, young patients (aged 2-32 years) with segmental deletions of FOXF2 showed an extensive burden of white matter hyperintensity. Deletion of Foxf2 in adult mice resulted in cerebral infarction, reactive gliosis, and microhaemorrhage. The orthologs of FOXF2 in zebrafish (foxf2b and foxf2a) are expressed in brain pericytes and mutant foxf2b(-/-) cerebral vessels show decreased smooth muscle cell and pericyte coverage. INTERPRETATION: We identified common variants near FOXF2 that are associated with increased stroke susceptibility. Epidemiological and experimental data suggest that FOXF2 mediates this association, potentially via differentiation defects of cerebral vascular mural cells. Further expression studies in appropriate human tissues, and further functional experiments with long follow-up periods are needed to fully understand the underlying mechanisms

Incremental effects of endocrine and metabolic biomarkers and abdominal obesity on cardiovascular mortality prediction.

BACKGROUND: Biomarkers may help clinicians predict cardiovascular risk. We aimed to determine if the addition of endocrine, metabolic, and obesity-associated biomarkers to conventional risk factors improves the prediction of cardiovascular and all-cause mortality. METHODOLOGY/PRINCIPAL FINDINGS: In a population-based cohort study (the Study of Health in Pomerania) of 3,967 subjects (age 20-80 years) free of cardiovascular disease with a median follow-up of 10.0 years (38,638 person-years), we assessed the predictive value of conventional cardiovascular risk factors and the biomarkers thyrotropin; testosterone (in men only); insulin-like growth factor-1 (IGF-1); hemoglobin A1c (HbA1c); creatinine; high-sensitive C-reactive protein (hsCRP); fibrinogen; urinary albumin-to-creatinine ratio; and waist-to-height ratio (WHtR) on cardiovascular and all-cause death. During follow-up, we observed 339 all-cause including 103 cardiovascular deaths. In Cox regression models with conventional risk factors, the following biomarkers were retained as significant predictors of cardiovascular death after backward elimination: HbA1c, IGF-1, and hsCRP. IGF-1 and hsCRP were retained as significant predictors of all-cause death. For cardiovascular death, adding these biomarkers to the conventional risk factors changed the C-statistic from 0.898 to 0.910 (p = 0.02). The net reclassification improvement was 10.6%. For all-cause death, the C-statistic changed from 0.849 to 0.853 (P = 0.09). CONCLUSIONS/SIGNIFICANCE: HbA1c, IGF-1, and hsCRP predict cardiovascular death independently of conventional cardiovascular risk factors. These easily assessed endocrine and metabolic biomarkers might improve the ability to predict cardiovascular death

Changes in Body Weight and Composition Are Associated With Changes in Left Ventricular Geometry and Function in the General Population

Background-The different effects of total body weight (TBW), fat-free mass (FFM), and fat mass (FM) on left ventricular (LV) geometry and function are complex. We investigated the associations of changes over time in TBW, FM, and FFM with changes in LV geometry and function. Methods and Results-We analyzed data from 1189 subjects (694 women), aged 44 to 86 years, from the baseline and the 5-year follow-up examination of the population-based SHIP (Study of Health in Pomerania). TBW was measured, and FFM and FM were calculated based on height-weight models derived from bioelectrical impedance studies. Echocardiographic measurements of LV geometry and function were performed according to the guidelines of the American Society of Echocardiography. Changes in body composition measures were associated with changes in LV geometry and function by multivariable-adjusted linear regression models. A 1-kg increase/decrease in TBW or FM was associated, respectively, with an increase/decrease of 0.89 g or 1.84 g in LV mass, whereas there was no such association on changes in FFM. Moreover, an increase in FM was associated with LV concentric remodeling and impairment of systolic and diastolic function parameters, whereas an increase in FFM was associated with LV eccentric remodeling and improved systolic and diastolic functional variables. Conclusions-Our findings indicate that changes in LV morphology and function depend on the type of body mass composition. Prospective data need to address whether specific changes in body composition over time may affect the risk for heart dysfunction more precisely than the change in TBW

Sex-specific associations of cardiorespiratory fitness and galectin-3 in the general population

Aims Low cardiorespiratory fitness (CRF) is associated with greater mortality and morbidity. Galectin-3 (Gal-3) is a prognostic biomarker for fibrosis and heart failure. Gal-3 is also associated with a greater risk for cardiovascular mortality. Whether CRF is related with Gal-3 is unclear. The objective of this study was to assess the sex-specific associations of CRF and Gal-3 levels in the general population. Methods Gal-3 concentrations were determined using a sandwich enzyme immunoassay in the population-based Study of Health in Pomerania (SHIP-TREND-0). Sex-stratified linear regression models adjusted for age, current smoking status, and renal function were used. Individuals with left ventricular ejection fraction (LVEF) 99th percentile) were excluded. Results A total of n = 1515 participants with a median age of 49 (IQR: 39–60 years, 48% males) were included. In men, a 1 L/min greater VO2peak was significantly related to 0.50 ng/mL (95% CI −0.8068 to −0.1938, P < 0.01) less Gal-3. In males, a 1 mL/min/kg higher VO2peak adjusted for body weight was associated with −0.0286 ng/mL (95% CI −0.0052 to −0.0005, P = 0.02) less Gal-3. When VO2peak was adjusted for lean mass 1 mL/kg/min more was correlated with a −0.0022 ng/mL (95% CI −0.0043 to -0.0007, P = 0.04) less Gal-3. In women, VO2peak (β −0.2046 95% CI −0.6541 to 0.2449, P = 0.37) and VO2peak adjusted for lean mass (β −0.0019 95% CI −0.0421 to –0.0050, P = 0.12) were not related with Gal-3, whereas a 1 mL/min/kg higher VO2peak adjusted for body weight was significantly associated with a −0.0064 ng/mL lower Gal-3 (95% CI −0.0092 to -0.0035, P < 0.01). There were no differences between pre-menopausal and post-menopausal women. Conclusions VO2peak was associated with Gal-3 only in men, but VO2peak adjusted for body weight in women and men. Our results suggest that the adverse consequences of low CRF may be mediated by Gal-3. Further research is needed to understand the sex-specific association between CRF and Gal-3 and whether they are clinically relevant

Effects of Apolipoprotein E polymorphism on carotid intima-media thickness, incident myocardial infarction and incident stroke

The Apolipoprotein E (APOE) gene polymorphism (rs429358 and rs7412) shows a well-established association with lipid profiles, but its effect on cardiovascular disease is still conflicting. Therefore, we examined the association of different APOE alleles with common carotid artery intima-media thickness (CCA-IMT), carotid plaques, incident myocardial infarction (MI) and stroke. We analyzed data from 3327 participants aged 20–79 years of the population-based Study of Health in Pomerania (SHIP) from Northeast Germany with a median follow-up time of 14.5 years. Linear, logistic, and Cox-regression models were used to assess the associations of the APOE polymorphism with CCA-IMT, carotid plaques, incident MI and stroke, respectively. In our study, the APOE E2 allele was associated with lower CCA-IMT at baseline compared to E3 homozygotes (β: − 0.02 [95% CI − 0.04, − 0.004]). Over the follow-up, 244 MI events and 218 stroke events were observed. APOE E2 and E4 allele were not associated with incident MI (E2 HR: 1.06 [95% CI 0.68, 1.66]; E4 HR: 1.03 [95% CI 0.73, 1.45]) and incident stroke (E2 HR: 0.79 [95% CI 0.48, 1.30]; E4 HR: 0.96 [95% CI 0.66, 1.38]) in any of the models adjusting for potential confounders. However, the positive association between CCA-IMT and incident MI was more pronounced in E2 carriers than E3 homozygotes. Thus, our study suggests that while APOE E2 allele may predispose individuals to lower CCA-IMT, E2 carriers may be more prone to MI than E3 homozygotes as the CCA-IMT increases. APOE E4 allele had no effect on CCA-IMT, plaques, MI or stroke