Questionnaire survey on cardiologists' view and management of coronary microvascular disease in clinical practice.

OBJECTIVE: We aimed to assess the opinion of Dutch cardiologists on coronary microvascular disease (CMD) and its management in clinical practice, and to assess the need for a CMD guideline among Dutch cardiologists. METHODS: We developed an online questionnaire including different aspects of CMD which was reviewed by an expert panel. The questionnaire was distributed by e­mail among all members of the Dutch Society of Cardiology. RESULTS: A total of 103 cardiologists (70% male) completed the questionnaire (response rate: 10%). Median age and years of experience as a cardiologist were 49 ± 15 and 12 ± 12 years, respectively. Overall, 93% of the cardiologists had considered the CMD diagnosis, 85% had ever made such a diagnosis, 90% had treated a patient with CMD, and 61% had referred patients to tertiary care. The median (interquartile range) self-rated knowledge level was 7.0 (2.0) (scale of 0-10). 84% rated their knowledge as sufficient (>5.5) and 58% viewed CMD as a disease entity. Overall, 61% and 17%, respectively, agreed that evidence-based diagnostic and treatment modalities for CMD do not exist, while 56% believed that CMD patients have a higher risk for cardiovascular disease and mortality. Finally, 82% of the responders stated that a CMD guideline is needed, and 91% wanted to receive the guideline once developed. DISCUSSION: Fifty-eight per cent of the responders recognise CMD as a separate disease entity. Our study underscores the need for a dedicated CMD guideline for Dutch cardiology practice. However, the response rate was low (10%), and it is likely that mainly cardiologists interested in CMD have participated in our study.

Development of a prediction model for future risk of radiographic hip osteoarthritis.

OBJECTIVE: To develop and validate a prognostic model for incident radiologic hip osteoarthritis (HOA) and determine the value of previously identified predictive factors. DESIGN: We first validated previously reported predictive factors for HOA by performing univariate and multivariate analyses for all predictors in three large prospective cohorts (total sample size of 4548 with 653 incident cases). The prognostic model was developed in 2327 individuals followed for 10 years from the Rotterdam Study-I (RS-I) cohort. External validation of the model was tested on discrimination in two other cohorts: RS-II (n = 1435) and the Cohort Hip and Cohort Knee (CHECK) study (n = 786). RESULTS: From the total number of 28 previously reported predictive factors, we were able to replicate 13 factors, while 15 factors were not significantly predictive in a meta-analysis of the three cohorts. The basic model including the demographic, questionnaire, and clinical examination variables (area under the receiver-operating characteristic curve (AUC) = 0.67) or genetic markers (AUC = 0.55) or urinary C-terminal cross-linked telopeptide of type II collagen (uCTX-II) levels (AUC = 0.67) alone were poor predictors of HOA in all cohorts. Imaging factors showed the highest predictive value for the development of HOA (AUC = 0.74). Addition of imaging variables to the basic model led to substantial improvement in the discriminative ability of the model (AUC = 0.78) compared with uCTX-II (AUC = 0.74) or genetic markers (AUC = 0.68). Applying external validation, similar results were observed in the RS-II and the CHECK cohort. CONCLUSIONS: The developed prediction model included demographic, a limited number of questionnaire, and imaging risk factors seems promising for prediction of HOA.

Exome-sequencing in a large population-based study reveals a rare Asn396Ser variant in the LIPG gene associated with depressive symptoms.

Despite a substantial genetic component, efforts to identify common genetic variation underlying depression have largely been unsuccessful. In the current study we aimed to identify rare genetic variants that might have large effects on depression in the general population. Using high-coverage exome-sequencing, we studied the exonic variants in 1265 individuals from the Rotterdam study (RS), who were assessed for depressive symptoms. We identified a missense Asn396Ser mutation (rs77960347) in the endothelial lipase (LIPG) gene, occurring with an allele frequency of 1% in the general population, which was significantly associated with depressive symptoms (P-value=5.2 × 10-08, ß=7.2). Replication in three independent data sets (N=3612) confirmed the association of Asn396Ser (P-value=7.1 × 10-03, ß=2.55) with depressive symptoms. LIPG is predicted to have enzymatic function in steroid biosynthesis, cholesterol biosynthesis and thyroid hormone metabolic processes. The Asn396Ser variant is predicted to have a damaging effect on the function of LIPG. Within the discovery population, carriers also showed an increased burden of white matter lesions (P-value=3.3 × 10-02) and a higher risk of Alzheimer's disease (odds ratio=2.01; P-value=2.8 × 10-02) compared with the non-carriers. Together, these findings implicate the Asn396Ser variant of LIPG in the pathogenesis of depressive symptoms in the general population.

Obesity in older adults and life expectancy with and without cardiovascular disease.

BACKGROUND: The prevalence of overweight and obesity is increasing globally and is an established risk factor for cardiovascular disease (CVD). Our objective was to evaluate the impact of overweight and obesity on life expectancy and years lived with and without CVD in older adults. METHODS: The study included 6636 individuals (3750 women) aged 55 years and older from the population-based Rotterdam Study. We developed multistate life tables by using prevalence, incidence rate and hazard ratios (HR) for three transitions (free-of-CVD-to-CVD, free-of-CVD-to-death and CVD-to-death), stratifying by the categories of body mass index (BMI) at baseline and adjusting for confounders. RESULTS: During 12 years of follow-up, we observed 1035 incident CVD events and 1902 overall deaths. Obesity was associated with an increased risk of CVD among men (HR 1.57 (95% confidence interval (CI) 1.17, 2.11)) and women (HR 1.49 (95% CI 1.19, 1.86)), compared with normal weight individuals. Overweight and obesity were not associated with mortality in men and women without CVD. Among men with CVD, obesity compared with normal weight, was associated with a lower risk of mortality (HR 0.67 (95% CI 0.49, 0.90)). Overweight and obesity did not influence total life expectancy. However, obesity was associated with 2.6 fewer years (95% CI -4.8, -0.4) lived free from CVD in men and 1.9 (95% CI -3.3, -0.9) in women. Moreover, men and women with obesity lived 2.9 (95% CI 1.1, 4.8) and 1.7 (95% CI 0.6, 2.8) more years suffering from CVD compared with normal weight counterparts. CONCLUSIONS: Obesity had no effect on total life expectancy in older individuals, but increased the risk of having CVD earlier in life and consequently extended the number of years lived with CVD. Owing to increasing prevalence of obesity and improved treatment of CVD, we might expect more individuals living with CVD and for a longer period of time.

Disability and not osteoarthritis predicts cardiovascular disease: a prospective population-based cohort study.

BACKGROUND: Previous studies found an association between osteoarthritis (OA) and risk of cardiovascular disease (CVD) and therefore suggested intensive treatment of cardiovascular risk factors in OA patients. However, prospective population-based data is lacking. OBJECTIVES: To investigate the association between OA and CVD longitudinally in a general population and examine the role of disability in this association. METHODS: This study was embedded in the Rotterdam Study, a prospective population-based cohort study in Rotterdam, the Netherlands that started in 1989. At baseline 4648 persons aged ≥55, free of CVD were classified into those with and those without radiographic or clinical OA. HRs adjusted for traditional cardiovascular risk factors for developing CVD (a composite of fatal and non-fatal coronary heart disease and stroke) were calculated. RESULTS: During a median follow-up of 14.4 years, 1230 cardiovascular events occurred, of which 101 were in participants with clinical OA. Presence of radiographic OA at baseline was not related to future CVD (HR 0.99, 95% CI 0.86 to 1.15), neither was presence of clinical OA (HR 1.09, 95% CI 0.88 to 1.34). However, persons with increasing disability were more likely to suffer a cardiovascular event compared with non-disabled persons (HR 1.26, 95% CI 1.12 to 1.42); this was independent of the presence of OA. CONCLUSIONS: In this large population-based study, participants with OA were not at increased risk of CVD. The close relation between disability and osteoarthritis may explain previous findings. Further studies are required in order to clarify whether OA patients need more intensive treatment of their cardiovascular risk factors.

Androgen levels in women with various forms of ovarian dysfunction: associations with cardiometabolic features.

STUDY QUESTION: Are differences in androgen levels among women with various forms of ovarian dysfunction associated with cardiometabolic abnormalities? SUMMARY ANSWER: Androgen levels differed substantially between women with and without ovarian dysfunction, and increased androgen levels were associated with impaired cardiometabolic features in all women irrespective of their clinical condition. WHAT IS KNOWN ALREADY: Sex steroid hormones play important roles in the development of cardiovascular diseases (CVD). Extremes of low as well as high androgen levels have been associated with increased CVD risk in both men and women. STUDY DESIGN, SIZE, DURATION: This cross-sectional study included 680 women with polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI), natural post-menopausal women (NM), or regular menstrual cycles (RC) (170 women per group). PARTICIPANTS/MATERIALS, SETTING, METHODS: Measurements of serum testosterone, androstenedione and dehydroepiandrosterone sulfate were performed using liquid chromatography-tandem mass spectrometry. Assessments were taken of body mass index (BMI), blood pressure, lipid profiles, glucose, insulin and SHBG, and the bioactive fraction of circulating testosterone was calculated using the free androgen index (FAI). MAIN RESULTS AND THE ROLE OF CHANCE: PCOS women were hyperandrogenic [median FAI = 4.9 (IQR 3.6-7.4)], and POI women were hypoandrogenic [FAI = 1.2 (0.8-1.7)], compared with RC women [FAI = 1.7 (1.1-2.8)], after adjustment for age, ethnicity, smoking and BMI (P < 0.001). After adjustment for age, there were no significant differences in androgens between POI and NM (P = 0.15) women and between NM and RC (P = 0.27) women, the latter indicating that chronological aging rather than ovarian aging influences the differences between pre- and post-menopausal women. A high FAI was associated with elevated triglycerides (ß log FAI for PCOS: 0.45, P < 0.001, POI: 0.25, P < 0.001, NM: 0.20, P = 0.002), insulin (ß log FAI for PCOS: 0.77, POI: 0.44, NM: 0.40, all P < 0.001), HOMA-IR (ß log FAI for PCOS: 0.82, POI: 0.46, NM: 0.47, all P < 0.001) and mean arterial pressure (ß log FAI for PCOS: 0.05, P = 0.002, POI: 0.07, P < 0.001, NM: 0.04, P = 0.04) in all women; with increased glucose (ß log FAI for PCOS: 0.05, P = 0.003, NM: 0.07, P < 0.001) and decreased high-density lipoprotein (ß log FAI for PCOS: -0.23, P < 0.001, NM: -0.09, P = 0.03) in PCOS and NM women; and with increased low-density lipoprotein (ß log FAI for POI: 0.083, P = 0.041) in POI women. Adjustment for BMI attenuated the observed associations. Associations between FAI and cardiometabolic features were the strongest in PCOS women, even after adjustment for BMI. LIMITATIONS, REASONS FOR CAUTION: Associations between androgen levels and cardiometabolic features were assessed in PCOS, POI and NM women only, due to a lack of available data in RC women. Due to the cross-sectional design of the current study, the potential associations between androgen levels and actual future cardiovascular events could not be assessed. WIDER IMPLICATIONS OF THE FINDINGS: This study affirms the potent effect of androgens on cardiometabolic features, indicating that androgens should indeed be regarded as important denominators of women's health. Future research regarding the role of androgens in the development of CVD and potential modulatory effects of BMI is required. STUDY FUNDING/COMPETING INTERESTS: N.M.P.D. is supported by the Dutch Heart Foundation (grant number 2013T083). L.J. and O.H.F. work in ErasmusAGE, a center for aging research across the life course, funded by Nestlé Nutrition (Nestec Ltd), Metagenics Inc. and AXA. M.K. is supported by the AXA Research Fund. Nestlé Nutrition (Nestec Ltd), Metagenics Inc. and AXA had no role in the design and conduct of the study; the collection, management, analysis and interpretation of the data; or the preparation, review or approval of the manuscript. J.S.E.L. has received fees and grant support from the following companies (in alphabetical order): Ferring, Merck-Serono, Merck Sharpe & Dome, Organon, Schering Plough and Serono. In the last 5 years, B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order); Actavis, COGI, Euroscreen, Ferring, Finox, Genovum, Gedeon-Richter, Merck-Serono, OvaScience, Pantharei Bioscience, PregLem, Roche, Uteron and Watson laboratories. With regard to potential conflicts of interest, there is nothing further to disclose.

N-terminal pro-B-type natriuretic peptide and the risk of stroke and transient ischaemic attack: the Rotterdam Study.

BACKGROUND AND PURPOSE: Amino-terminal pro-B-type natriuretic peptide (NT-proBNP) is a predictor of heart disease. It has also been related to stroke, but its association with transient ischaemic attacks (TIAs) is unclear. Moreover, it is unknown how clinical heart disease influences this relation. Within the prospective population-based Rotterdam Study, the association of NT-proBNP with stroke and TIA was examined and the role of heart disease on this association was investigated. METHODS: NT-proBNP was measured in 1997-2001 in 5611 participants (mean age 68.7 years; 57.7% women) without a history of stroke, TIA or heart failure. Follow-up for stroke and TIA finished in 2012. Models were adjusted for age and cardiovascular risk factors, and were stratified by sex. RESULTS: During 22 058 person-years 195 men suffered a stroke and 118 a TIA. During 31 825 person-years 230 women suffered a stroke and 187 a TIA. Higher NT-proBNP was associated with a higher risk of stroke in men [hazard ratio (HR) per SD increase 1.50; 95% confidence interval (CI) 1.29-1.76] and in women (HR 1.24; 95% CI 1.05-1.46). Associations with TIA were only present in women (HR 1.51; 95% CI 1.26-1.82) but not in men (HR 1.02; 95% CI 0.83-1.26). Excluding persons with a history of clinical coronary heart disease, heart failure or atrial fibrillation and censoring for clinical heart disease during follow-up did not change the associations. CONCLUSIONS: Higher NT-proBNP is associated with incident stroke in men and women and with incident TIA only in women. These associations are independent of clinical heart disease preceding cerebrovascular disease.

Evaluation pattern within tumor microenvironment and consequent gene expression in oral cancer.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is one of the most common cancers in the head and neck squamous cell cancer group. The increasing frequency of oral carcinomas and their late-stage appearance is a major worldwide health concern. MicroRNAs (miRNAs) appear to play an important role in cancer growth and progression, according to growing data, whereas no information is available regarding miR-7113-3p and miR-6721-5p involvement in OSCC. In this article, the expression of MAP2K1, miR-7113-3p, and miR-6721-5p was examined for possible bio-logical functions in the advancement of oral squamous cell carcinoma. MATERIAL AND METHODS: We used quantitative real-time PCR (to examine the mRNA expression of MAP2K1, miR-7113-3p, and miR-6721-5p in fresh frozen OSCC tissues and adjacent normal fresh frozen tissues from 30 patients, and we investigated their relationship with clinical parameters. RESULTS: MAP2K1 expression was found to be dramatically increased in tumor tissues than in normal tissues, whereas miR7113-3p and miR-6721-5p expression was significantly decreased. Furthermore, a statistical correlation of P = 0.04 was also observed between increased MAP2K1 expression and perineural invasion. Additionally, we noted that the downregulation of miR-7113-3p appears to correlate positively with overexpression of MAP2K1 (P = 0.0218), and a negative correlation was observed between downregulation of miR-6721-5p and overexpression of MAP2K1 (P = 0.7771). CONCLUSION: Based on these findings, miR-7113-3p and miR-6721-5p might be prospective bio-markers for OSCC patients, and could be utilized to detect OSCC at an early stage for future dia-gnosis. MAP2K1 overexpression has been linked to the development of OSCC and perineural invasion.

Sex-related differences in coronary and carotid vessel geometry, plaque composition and shear stress obtained from imaging.

Atherosclerosis manifests itself differently in men and women with respect to plaque initiation, progression and plaque composition. The observed delay in plaque progression in women is thought to be related to the hormonal status of women. Also features associated with the vulnerability of plaques to rupture seem to be less frequently present in women compared to men. Current invasive and non-invasive imaging modalities allow for visualization of plaque size, composition and high risk vulnerable plaque features. Moreover, image based modeling gives access to local shear stress and shear stress-related plaque growth. In this review, current knowledge on sex-related differences in plaque size, composition, high risk plaque features and shear stress related plaque growth in carotid and coronary arteries obtained from imaging are summarized.

Common carotid intima-media thickness does not add to Framingham risk score in individuals with diabetes mellitus: the USE-IMT initiative.

AIMS/HYPOTHESIS: The aim of this work was to investigate whether measurement of the mean common carotid intima-media thickness (CIMT) improves cardiovascular risk prediction in individuals with diabetes. METHODS: We performed a subanalysis among 4,220 individuals with diabetes in a large ongoing individual participant data meta-analysis involving 56,194 subjects from 17 population-based cohorts worldwide. We first refitted the risk factors of the Framingham heart risk score on the individuals without previous cardiovascular disease (baseline model) and then expanded this model with the mean common CIMT (CIMT model). The absolute 10 year risk for developing a myocardial infarction or stroke was estimated from both models. In individuals with diabetes we compared discrimination and calibration of the two models. Reclassification of individuals with diabetes was based on allocation to another cardiovascular risk category when mean common CIMT was added. RESULTS: During a median follow-up of 8.7 years, 684 first-time cardiovascular events occurred among the population with diabetes. The C statistic was 0.67 for the Framingham model and 0.68 for the CIMT model. The absolute 10 year risk for developing a myocardial infarction or stroke was 16% in both models. There was no net reclassification improvement with the addition of mean common CIMT (1.7%; 95% CI -1.8, 3.8). There were no differences in the results between men and women. CONCLUSIONS/INTERPRETATION: There is no improvement in risk prediction in individuals with diabetes when measurement of the mean common CIMT is added to the Framingham risk score. Therefore, this measurement is not recommended for improving individual cardiovascular risk stratification in individuals with diabetes.

Investigating changes in the post-transcriptional pattern of VEGF and CD146 genes carrying miR-573 in breast cancer cells treated with tamoxifen.

BACKGROUND: Recent developments regarding the contribution of microRNAs (miRNAs) to tumor angiogenesis and the oncogenic effects of miRNAs point to their potential role in breast cancer angiogenesis. Tumor-derived exosomes are considered a rich source of miRNAs that can regulate the function of other cells in the tumor microenvironment, including vascular endothelial cells. This study analyzes the effect of tamoxifen chemotherapy on the expression of a key miRNA, miR-573, involved in the angiogenesis of the tumor exosomes and introduces a regulatory link between this miRNA and the CD146 gene associated with the vascular endothelial growth factor (VEGF) messaging pathway. MATERIALS AND METHODS: MCF-7 breast cancer cells were purchased and cultured in a complete culture medium. These cells were treated with tamoxifen and then their exosomes were extracted from the culture medium. The RNAs of the exosomes were isolated and the expression of miR-573, VEGF, and CD146 genes in the exosomes was investigated using the real-time polymerase chain reaction (PCR) method. RESULTS: The results of this study showed that tamoxifen treatment increased the expression of miR-573 in exosomes derived from MCF-7 cancer cells. The expression of CD146 and VEGF genes in drug-treated cell exosomes had a downward pattern. CONCLUSION: The results of this experiment demonstrated that the treatment of breast cancer cells with tamoxifen reduces the expression of VEGF and CD146 by increasing miR-573. Thus, angiogenesis is reduced and, therefore, its anti-tumor effects are applied.

Study of KDM1A and VEGF changes as the responsible genes in the angiogenesis of breast cancer.

BACKGROUND: Recent developments regarding the contribution of microRNAs to tumor angiogenesis and the oncogenic effects of microRNAs point to their potential role in breast cancer angiogenesis. Tumor-derived exosomes are considered a rich source of microRNAs that can regulate the function of other cells in the tumor microenvironment, including vascular endothelial cells. This study analyzes the effect of tamoxifen chemotherapy on the expression of a key microRNA, miR-329, and introduces a regulatory link between this microRNA and the KDM1A gene associated with the vascular endothelial growth factor (VEGF) messaging pathway. MATERIALS AND METHODS: MCF-7 breast cancer cells were purchased and cultured in a complete culture medium. These cells were treated with tamoxifen and then their exosomes were extracted from the culture medium. The RNAs of the exosomes were isolated and the expression of miR-329, VEGF, and KDM1A genes in the exosomes was investigated using the real-time polymerase chain reaction (PCR) method. RESULTS: The results of this study showed that tamoxifen treatment increased the expression of miR-329 in exosomes derived from MCF-7 cancer cells. The expression of KDM1A and VEGF genes in drug-treated cell exosomes is downregulated. CONCLUSION: The results of this experiment demonstrated that the treatment of breast cancer cells with tamoxifen reduces the expression of VEGF and KDM1A by increasing miR-329. The treatment therefore reduces angiogenesis, and thus its anti-tumor effects are applied.

Extra-cellular exosomes may have the role of a carrier in transferring molecules from the tumor micro-environment to the unaffected cells in breast cancer tumors.

BACKGROUND: Breast cancer is recognized as a major clinical challenge in gynecological diseases worldwide. Exosomes are small vesicles derived from multicellular bodies that are secreted by many cells into the extracellular environment and thus participate in intercellular communication through the transfer of genetic information such as encoded and non-encoded RNAs to target cells. Tumor-derived exosomes are thought to be a rich source of microRNAs (miRNAs) that can regulate the function of other cancer cells in the tumor microenvironment. However, the exact mechanisms by which tumor cell-derived exosomes affect their neighboring cells, as well as the biological function of exosomal miRNAs in receptor cells, are not well understood. MATERIALS AND METHODS: In this study, after overexpression of miR-205 in breast cancer cells (MDA-MB-231 class), cell-derived exosomes were successfully isolated and characterized by electron microscopy and dynamic light scattering. RESULTS: Determination of miR-205 expression levels in exosomes secreted from engineered cells confirmed the high expression of this miRNA in exosomes. It was also found that treatment of tumor exosomes carrying this miRNA had an apoptotic induction effect and also had a significant effect on reducing the expression of Bcl-2 gene transcript in a time-dependent manner in breast cancer cells (P < 0.001). CONCLUSION: Overall, this study suggests that exosomal transfer of tumor suppressor miRNAs to cancer cells could be a suitable platform for nucleic acid transfer to these cells and be highly effective in cancer treatment.

Sex steroids and markers of micro- and macrovascular damage among women and men from the general population.

AIMS: The contribution of sex hormones to micro- and macrovascular damage might differ among women and men. In particular, little is known about the association between sex hormones and small vessel disease. Therefore, we examined the association of total oestradiol, total testosterone, free-androgen index (FAI), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), and androstenedione levels with micro- and macrovascular diseases. METHODS AND RESULTS: This cross-sectional study included 2950 women and 2495 men from the population-based Rotterdam Study. As proxy of microvascular damage, we measured diameters of retinal arterioles and venules. Markers of macrovascular damage included carotid intima-media thickness and carotid plaque, coronary artery calcification (CAC), and peripheral artery disease. Linear and logistic regression models were used and adjusted for age, cardiovascular risk factors, and years since menopause. Associations with microvasculature: In women, total testosterone [mean difference per 1-unit increase in natural-log transformed total testosterone (95% confidence interval, CI): 2.59 (0.08-5.09)] and androstenedione [4.88 (1.82-7.95)] and in men DHEAS [2.80 (0.23-5.37)] and androstenedione [5.83 (2.19-9.46)] were associated with larger venular caliber. Associations with markers of large vessel disease: In women, higher total testosterone [-0.29 (-0.56 to -0.03)], FAI [-0.33 (-0.56 to -0.10)], and androstenedione levels [-0.33 (-0.64 to -0.02)] were associated with lower CAC burden and FAI [odds ratio (95% CI): 0.82 (0.71-0.94)] was associated with lower prevalence of plaque. CONCLUSION: A more androgenic profile was associated with more microvascular damage in both women and men. Among women, however, higher androgen levels were also associated with less macrovascular damage. Our findings suggest that androgens might have distinct effects on the vasculature, depending on the vascular bed and stages of the atherosclerosis process.

Resting heart rate and incident atrial fibrillation: A stratified Mendelian randomization in the AFGen consortium.

BACKGROUND: Both elevated and low resting heart rates are associated with atrial fibrillation (AF), suggesting a U-shaped relationship. However, evidence for a U-shaped causal association between genetically-determined resting heart rate and incident AF is limited. We investigated potential directional changes of the causal association between genetically-determined resting heart rate and incident AF. METHOD AND RESULTS: Seven cohorts of the AFGen consortium contributed data to this meta-analysis. All participants were of European ancestry with known AF status, genotype information, and a heart rate measurement from a baseline electrocardiogram (ECG). Three strata of instrumental variable-free resting heart rate were used to assess possible non-linear associations between genetically-determined resting heart rate and the logarithm of the incident AF hazard rate: <65; 65-75; and >75 beats per minute (bpm). Mendelian randomization analyses using a weighted resting heart rate polygenic risk score were performed for each stratum. We studied 38,981 individuals (mean age 59±10 years, 54% women) with a mean resting heart rate of 67±11 bpm. During a mean follow-up of 13±5 years, 4,779 (12%) individuals developed AF. A U-shaped association between the resting heart rate and the incident AF-hazard ratio was observed. Genetically-determined resting heart rate was inversely associated with incident AF for instrumental variable-free resting heart rates below 65 bpm (hazard ratio for genetically-determined resting heart rate, 0.96; 95% confidence interval, 0.94-0.99; p = 0.01). Genetically-determined resting heart rate was not associated with incident AF in the other two strata. CONCLUSIONS: For resting heart rates below 65 bpm, our results support an inverse causal association between genetically-determined resting heart rate and incident AF.

Reporting of sex-specific outcomes in trials of interventions for cardiovascular disease: Has there been progress?

In the past decade, the leading international cardiology societies have released statements that emphasize the importance of sex-specific reporting of the findings of clinical trials in cardiovascular research. To find out whether this has led to improvement, we compared sex-specific reporting of efficacy and safety outcomes for trials of cardiovascular drug interventions presented at the major clinical trials sessions of the European Society of Cardiology (ESC), American Heart Association (AHA) and the American College of Cardiology (ACC) before and after publication of these statements. We found that sex-specific efficacy and safety outcomes of the most influential cardiovascular intervention trials are still not systematically presented.

Physical activity types and atrial fibrillation risk in the middle-aged and elderly: The Rotterdam Study.

Background The association between physical activity and atrial fibrillation remains controversial. Physical activity has been associated with a higher and lower atrial fibrillation risk. These inconsistent results might be related to the type of physical activity. We aimed to investigate the association of total and types of physical activity, including walking, cycling, domestic work, gardening and sports, with atrial fibrillation. Design Prospective cohort study. Methods Our study was performed in the Rotterdam Study, a prospective population-based cohort. We included 7018 participants aged 55 years and older with information on physical activity between 1997-2001. Cox proportional hazards models were used to examine the association of physical activity with atrial fibrillation risk. Models were adjusted for biological and behavioural risk factors and the remaining physical activity types. Physical activity was categorised in tertiles and the low group was used as reference. Results During 16.8 years of follow-up (median: 12.3 years, interquartile range: 8.7-15.9 years), 800 atrial fibrillation events occurred (11.4% of the study population). We observed no association between total physical activity and atrial fibrillation risk in any model. After adjustment for confounders, the hazard ratio and 95% confidence interval for the high physical activity category compared to the low physical activity category was: 0.71 (0.80-1.14) for total physical activity. We did not observe a significant association between any of the physical activity types with atrial fibrillation risk. Conclusion Our results suggest that physical activity is not associated with higher or lower risk of atrial fibrillation in older adults. Neither total physical activity nor any of the included physical activity types was associated with atrial fibrillation risk.

Low ADAMTS-13 activity and the risk of coronary heart disease - a prospective cohort study: the Rotterdam Study.

Essentials An association between ADAMTS-13 and coronary heart disease (CHD) has been suggested. 5688 participants ≥ 55 years from the Rotterdam Study without a history of CHD were included. Over a median follow-up time of 9.7 years, 456 individuals suffered from CHD. Low ADAMTS-13 activity was associated with an increased CHD risk. SUMMARY: Background The metalloprotease ADAMTS-13 cleaves high-molecular-weight von Willebrand factor multimers into smaller, less procoagulant forms. Low ADAMTS-13 activity is associated with an increased risk of ischemic stroke but its pathogenic role in coronary heart disease (CHD) is unclear. Objectives We aimed to determine the association between ADAMTS-13 activity and the risk of CHD in a large prospective population-based cohort study. Methods A total of 5688 participants of the Rotterdam Study, a population-based cohort study involving individuals aged ≥ 55 years without a history of CHD, were included. ADAMTS-13 activity was measured by the FRETS-VWF73 assay and VWF:Ag levels by ELISA. We assessed the association between ADAMTS-13 activity, VWF:Ag levels and CHD using Cox proportional hazard regression analysis, adjusting for cardiovascular risk factors. Results Over a median follow-up time of 9.7 years, 456 individuals suffered from CHD. A low ADAMTS-13 activity (quartile 1) was associated with an increased CHD risk (HR 1.42, 95% CI 1.07-1.89) compared with the reference highest quartile. Conclusions Low ADAMTS-13 activity is associated with an increased risk of CHD in the elderly, independently of VWF and established cardiovascular risk factors.

von Willebrand factor plasma levels, genetic variations and coronary heart disease in an older population.

BACKGROUND: High von Willebrand factor (VWF) levels are associated with an increased risk of coronary heart disease (CHD). However, it remains unclear whether VWF is causally related to the occurrence of CHD or primarily mirrors endothelial dysfunction, which predisposes to atherosclerosis and subsequent CHD. OBJECTIVES: Because VWF is largely determined by genetic factors, we investigated whether VWF antigen levels (VWF:Ag) and the risk of CHD are affected by common variations in the VWF gene. METHODS: We included 7002 participants (≥ 55 years) from the large prospective population-based Rotterdam Study in the discovery cohort. The extension cohort of the Rotterdam Study, consisting of 3011 participants, was used as a replication cohort. We determined VWF:Ag levels and genotype data of 38 single-nucleotide polymorphisms (SNPs) in VWF. Subsequently, hazard ratios for CHD were calculated and genetic analyses were performed to assess the relationship between SNPs, VWF:Ag levels and CHD risk. RESULTS: We identified and replicated three SNPs that were associated with VWF:Ag: rs216321 (ß = 0.10 [95% confidence interval, CI, 0.06;0.13]) (Ala852Gln), rs1063856 (ß = 0.05 [95% CI 0.03;0.07]) (Thr789Ala) and rs2283333 (ß = 0.09 [95% CI 0.05;0.21]) (intron 15). However, genetic polymorphisms in the VWF gene were not associated with the risk of CHD. CONCLUSIONS: In this study we have shown that genetic variations in VWF strongly affect VWF plasma levels, but are not associated with the risk of CHD. Our findings therefore do not support a strong causal relationship between VWF and CHD in elderly individuals of ≥ 55 years, but suggest that VWF is primarily a marker of CHD.