Coronary calcification measures predict mortality in symptomatic women and men.

OBJECTIVE: To assess the prognostic value of absolute and sex-specific, age-specific and race/ethnicity-specific (Multi-Ethnic Study of Atherosclerosis, MESA) percentiles of coronary artery calcification in symptomatic women and men. METHODS: The study population consisted of 4985 symptomatic patients (2793 women, 56%) visiting a diagnostic outpatient cardiology clinic between 2009 and 2018 who were referred for cardiac CT to determine Coronary Artery Calcium Score (CACS). Regular care data were used and these data were linked to the databases of Statistics Netherlands for all-cause mortality data. Kaplan-Meier curves, multivariate Cox proportional hazards regression and concordance statistics were used to evaluate the prognostic value of CACS and MESA percentiles. Women were older compared with men (60 vs 59 years). RESULTS: Median CACS was 0 (IQR: 0-54) in women and 42 (IQR: 0-54) in men. After a median follow-up of 4.4 years (IQR: 3.1-6.3), 116 (2.3%; 53 women and 63 men) patients died. MESA percentiles did not perform better compared with absolute CACS (C-statistic 0.65, 95% CI 0.57 to 0.73, vs 0.66, 95% CI 0.58 to 0.74, in women and 0.59, 95% CI 0.51 to 0.67, vs 0.62, 95% CI 0.55 to 0.69, in men, for the percentiles and absolute CACS, respectively). CONCLUSIONS: In symptomatic individuals absolute CACS predicts mortality with a moderately good performance. MESA percentiles did not perform better compared with absolute CACS, thus there is no need to use them. Including degree of stenosis in the model might slightly improve mortality risk prediction in women, but not in men.

Development of a Pipeline for Adverse Drug Reaction Identification in Clinical Notes: Word Embedding Models and String Matching.

BACKGROUND: Knowledge about adverse drug reactions (ADRs) in the population is limited because of underreporting, which hampers surveillance and assessment of drug safety. Therefore, gathering accurate information that can be retrieved from clinical notes about the incidence of ADRs is of great relevance. However, manual labeling of these notes is time-consuming, and automatization can improve the use of free-text clinical notes for the identification of ADRs. Furthermore, tools for language processing in languages other than English are not widely available. OBJECTIVE: The aim of this study is to design and evaluate a method for automatic extraction of medication and Adverse Drug Reaction Identification in Clinical Notes (ADRIN). METHODS: Dutch free-text clinical notes (N=277,398) and medication registrations (N=499,435) from the Cardiology Centers of the Netherlands database were used. All clinical notes were used to develop word embedding models. Vector representations of word embedding models and string matching with a medical dictionary (Medical Dictionary for Regulatory Activities [MedDRA]) were used for identification of ADRs and medication in a test set of clinical notes that were manually labeled. Several settings, including search area and punctuation, could be adjusted in the prototype to evaluate the optimal version of the prototype. RESULTS: The ADRIN method was evaluated using a test set of 988 clinical notes written on the stop date of a drug. Multiple versions of the prototype were evaluated for a variety of tasks. Binary classification of ADR presence achieved the highest accuracy of 0.84. Reduced search area and inclusion of punctuation improved performance, whereas incorporation of the MedDRA did not improve the performance of the pipeline. CONCLUSIONS: The ADRIN method and prototype are effective in recognizing ADRs in Dutch clinical notes from cardiac diagnostic screening centers. Surprisingly, incorporation of the MedDRA did not result in improved identification on top of word embedding models. The implementation of the ADRIN tool may help increase the identification of ADRs, resulting in better care and saving substantial health care costs.

Preventing unnecessary imaging in patients suspect of coronary artery disease through machine learning of electronic health records.

Aims: With the ageing European population, the incidence of coronary artery disease (CAD) is expected to rise. This will likely result in an increased imaging use. Symptom recognition can be complicated, as symptoms caused by CAD can be atypical, particularly in women. Early CAD exclusion may help to optimize use of diagnostic resources and thus improve the sustainability of the healthcare system. To develop sex-stratified algorithms, trained on routinely available electronic health records (EHRs), raw electrocardiograms, and haematology data to exclude CAD in patients upfront. Methods and results: We trained XGBoost algorithms on data from patients from the Utrecht Patient-Oriented Database, who underwent coronary computed tomography angiography (CCTA), and/or stress cardiac magnetic resonance (CMR) imaging, or stress single-photon emission computerized tomography (SPECT) in the UMC Utrecht. Outcomes were extracted from radiology reports. We aimed to maximize negative predictive value (NPV) to minimize the false negative risk with acceptable specificity. Of 6808 CCTA patients (31% female), 1029 females (48%) and 1908 males (45%) had no diagnosis of CAD. Of 3053 CMR/SPECT patients (45% female), 650 females (47%) and 881 males (48%) had no diagnosis of CAD. On the train and test set, the CCTA models achieved NPVs and specificities of 0.95 and 0.19 (females) and 0.96 and 0.09 (males). The CMR/SPECT models achieved NPVs and specificities of 0.75 and 0.041 (females) and 0.92 and 0.026 (males). Conclusion: Coronary artery disease can be excluded from EHRs with high NPV. Our study demonstrates new possibilities to reduce unnecessary imaging in women and men suspected of CAD.

Plasma Testosterone Levels and Atherosclerotic Plaque Gene Expression in Men With Advanced Atherosclerosis.

Aims: Low plasma testosterone levels have been shown to predict worse outcome in men with severe atherosclerotic disease. We hypothesized that a low plasma testosterone level affects disease risk through changes in gene expression in atherosclerotic plaques. Therefore, we studied plasma testosterone levels in relation to gene expression levels in atherosclerotic plaque tissue of men with advanced atherosclerotic disease. Methods: Plasma testosterone levels were measured in 203 men undergoing carotid endarterectomy. The corresponding atherosclerotic plaque tissue was used for RNA sequencing. First, we assessed how often the androgen receptor gene was expressed in the plaque. Second, correlations between plasma testosterone levels and pre-selected testosterone-sensitive genes were assessed. Finally, differences within the RNA expression profile of the plaque as a whole, characterized into gene regulatory networks and at individual gene level were assessed in relation to testosterone levels. Results: Testosterone plasma levels were low with a median of 11.6 nmol/L (IQR: 8.6-13.8). RNA-seq of the plaque resulted in reliable expression data for 18,850 genes to be analyzed. Within the RNA seq data, the androgen-receptor gene was expressed in 189 out of 203 (93%) atherosclerotic plaques of men undergoing carotid endarterectomy. The androgen receptor gene expression was not associated with testosterone plasma levels. There were no significant differences in gene expression of atherosclerotic plaques between different endogenous testosterone levels. This remained true for known testosterone-sensitive genes, the complete transcriptomic profile, male-specific gene co-expression modules as well as for individual genes. Conclusion: In men with severe atherosclerotic disease the androgen receptor is highly expressed in plaque tissue. However, plasma testosterone levels were neither associated with pre-selected testosterone sensitive genes, gene expression profiles nor gene regulatory networks in late-stage atherosclerotic plaques. The effect of testosterone on gene expression of the late-stage atherosclerotic plaque appears limited, suggesting that alternate mechanisms explain its effect on clinical outcomes.

Persistent Symptoms and Health Needs of Women and Men With Non-Obstructed Coronary Arteries in the Years Following Coronary Angiography.

Background: The prognosis of women and men with persistent anginal complaints and non-obstructed coronary arteries is impaired as compared with asymptomatic women and men. The increased healthcare burden in the hospital due to repeated coronary angiography in these women and men has been documented, yet little is known about the percentage of women and men who remain symptomatic and under care of the general practitioner in the years following a coronary angiographic outcome of non-obstructed coronary arteries. Methods: From the Utrecht Coronary Biobank study, including individuals who underwent a coronary angiography from 2011 to 2015 (N = 2,546, 27% women), we selected women and men with non-obstructed coronary arteries (N = 687, 39% women). This population was linked to the Julius General Practitioners Network (JGPN); a database with routine care data of general practitioners. For every individual with non-obstructed coronary arteries, we selected an asymptomatic non-referred age-, sex-, and general practitioner-matched individual from the JGPN. We compared the healthcare consumption of men and women with non-obstructed coronary arteries to these matched individuals. The McNemar's test was used for pairwise comparison, and sex differences were assessed using stratified analyses. Results: The prevalence of non-obstructed coronary arteries was higher in women as compared with men (39 vs. 23%). During a median follow-up of 7 years [IQR 6.4-8.0], 89% of the individuals with non-obstructed coronary arteries (91% women and 87% men) visited their general practitioner for one or more cardiovascular consultations. This was compared to 34% of the matched individuals (89 vs. 34%, p < 0.001). The consultations were most often for angina (equivalents) (57 vs. 11%, p < 0.001) and heart failure (10 vs. 2%, p = 0.015). In addition, they more often consulted the general practitioner for psychosocial complaints (31 vs. 15%, p = 0.005). Findings were similar for women and men. Conclusions: A coronary angiographic outcome of non-obstructed coronary arteries is more common in women than in men. In the years following the coronary angiography, the majority of the population remains symptomatic. Both women and men with non-obstructed coronary arteries had higher health needs for angina, heart failure, and psychosocial complaints than matched asymptomatic individuals.

Cardiovascular imaging of women and men visiting the outpatient clinic with chest pain or discomfort: design and rationale of the ARGUS Study.

INTRODUCTION: Chest pain or discomfort affects 20%-40% of the general population over the course of their life and may be a symptom of myocardial ischaemia. For the diagnosis of obstructive macrovascular coronary artery disease (CAD), algorithms have been developed; however, these do not exclude microvascular angina. This may lead to false reassurance of symptomatic patients, mainly women, with functionally significant, yet non-obstructive coronary vascular disease. Therefore, this study aims to estimate the prevalence of both macrovascular and microvascular coronary vascular disease in women and men presenting with chest pain or discomfort, and to subsequently develop a decision-support tool to aid cardiologists in referral to cardiovascular imaging for both macrovascular and microvascular CAD evaluation. METHODS AND ANALYSIS: Women and men with chest pain or discomfort, aged 45 years and older, without a history of cardiovascular disease, who are referred to an outpatient cardiology clinic by their general practitioner are eligible for inclusion. Coronary CT angiography is used for anatomical imaging. Additionally, myocardial perfusion imaging by adenosine stress cardiac MRI is performed to detect functionally significant coronary vascular disease. Electronic health record data, collected during regular cardiac work-up, including medical history, cardiovascular risk factors, physical examination, echocardiography, (exercise) ECG and blood samples for standard cardiovascular biomarkers and research purposes, are obtained. Participants will be classified as positive or negative for coronary vascular disease based on all available data by expert panel consensus (a cardiovascular radiologist and two cardiologists). After completion of the clinical study, all collected data will be used to develop a decision support tool using predictive modelling and machine-learning techniques. ETHICS AND DISSEMINATION: The study protocol was approved by the Institutional Review Board of the University Medical Center Utrecht. Results will be disseminated through national and international conferences and in peer-reviewed journals in cardiovascular disease. TRIAL REGISTRATION NUMBER: Trialregister.nl Registry NL8702.

Coronary artery disease prediction in women and men using chest pain characteristics and risk factors: an observational study in outpatient clinics.

OBJECTIVES: To assess the diagnostic value of non-acute chest pain characteristics for coronary artery disease in women and men referred to outpatient cardiology clinics. DESIGN AND SETTING: This is an observational study performed at outpatient cardiology centres of the Netherlands. PARTICIPANTS: The study population consisted of 1028 patients with non-acute chest pain (505 women). ANALYSIS AND RESULTS: Twenty-four women (5%) and 75 men (15%) were diagnosed with coronary artery disease by invasive coronary angiography or CT angiography during regular care follow-up. Elastic net regression was performed to assess which chest pain characteristics and risk factors were of diagnostic value. The overall model selected age, provocation by temperature or stress, relief at rest and functional class as determinants and was accurate in both sexes (area under the curve (AUC) of 0.76 (95% CI 0.68 to 0.85) in women and 0.83 (95% CI 0.78 to 0.88) in men). Both sex-specific models selected age, pressuring nature, radiation, duration, frequency, progress, provocation and relief at rest as determinants. The female model additionally selected dyspnoea, body mass index, hypertension and smoking while the male model additionally selected functional class and diabetes. The sex-specific models performed better than the overall model, but more so in women (AUC: 0.89, 95% CI 0.81 to 0.96) than in men (AUC: 0.84, 95% CI 0.73 to 0.90). CONCLUSIONS: In both sexes, the diagnostic value of non-acute chest pain characteristics and risk factors for coronary artery disease was high. Provocation, relief at rest and functional class of chest pain were the most powerful diagnostic predictors in both women and men. When stratified by sex the performance of the model improved, mostly in women.

Sex-Specific Aspects in the Pathophysiology and Imaging of Coronary Macro- and Microvascular Disease.

Sex differences in coronary artery disease (CAD) are well established, with women presenting with non-obstructive CAD more often than men do. However, recent evidence has identified coronary microvascular dysfunction as the underlying cause for cardiac complaints, yet sex-specific prevalence numbers are inconclusive. This review summarises known sex-specific aspects in the pathophysiology of both macro- and microvascular dysfunction and identifies currently existing knowledge gaps. In addition, this review describes current diagnostic approaches and whether these should take underlying sex differences into account by, for example, using different techniques or cut-off values for women and men. Future research into both innovation of imaging techniques and perfusion-related sex differences is needed to fill evidence gaps and enable the implementation of the available knowledge in daily clinical practice.

Discovery of biomarkers for the presence and progression of left ventricular diastolic dysfunction and HEart faiLure with Preserved ejection Fraction in patients at risk for cardiovascular disease: rationale and design of the HELPFul case-cohort study in a Dutch cardiology outpatient clinic.

INTRODUCTION: Left ventricular diastolic dysfunction (LVDD) is a common condition in both sexes that may deteriorate into heart failure (HF) with preserved ejection fraction (pEF), although this seems to happen more often in women than in men. Both LVDD and HFpEF often go unrecognised, necessitating the discovery of biomarkers that aid both the identification of individuals with LVDD at risk of developing HF and identification of individuals most likely to benefit from treatment. METHODS AND ANALYSIS: HELPFul is an ongoing case-cohort study at a Dutch cardiology outpatient clinic enrolling patients aged 45 years and older without history of cardiovascular disease, who were referred by the general practitioner for cardiac evaluation. We included a random sample of patients and enriched the cohort with cases (defined as an E/e' ≥8 measured with echocardiography). Information about medical history, cardiovascular risk factors, electrocardiography, echocardiography, exercise test performance, common carotid intima-media thickness measurement and standard cardiovascular biomarkers was obtained from the routine care data collected by the cardiology outpatient clinic. Study procedure consists of extensive venous blood collection for biobanking and additional standardised questionnaires. Follow-up will consist of standardised questionnaires by mail and linkage to regional and national registries. We will perform cardiac magnetic resonance imaging and coronary CT angiography in a subgroup of patients to investigate the extent of macrovascular and microvascular coronary disease. ETHICS AND DISSEMINATION: The study protocol was approved by the Institutional Review Board of the University Medical Center Utrecht. Results will be disseminated through national and international conferences and in peer-reviewed journals in cardiovascular disease. TRIAL REGISTRATION: NTR6016;Pre-results.

Adverse Drug Reactions to Guideline-Recommended Heart Failure Drugs in Women: A Systematic Review of the Literature.

OBJECTIVES: This study sought to summarize all available evidence on sex differences in adverse drug reactions (ADRs) to heart failure (HF) medication. BACKGROUND: Women are more likely to experience ADRs than men, and these reactions may negatively affect women's immediate and long-term health. HF in particular is associated with increased ADR risk because of the high number of comorbidities and older age. However, little is known about ADRs in women with HF who are treated with guideline-recommended drugs. METHODS: A systematic search of PubMed and EMBASE was performed to collect all available information on ADRs to angiotensin-converting enzyme inhibitors, ß-blockers, angiotensin II receptor blockers, mineralocorticoid receptor antagonists, ivabradine, and digoxin in both women and men with HF. RESULTS: The search identified 155 eligible records, of which only 11 (7%) reported ADR data for women and men separately. Sex-stratified reporting of ADRs did not increase over the last decades. Six of the 11 studies did not report sex differences. Three studies reported a higher risk of angiotensin-converting enzyme inhibitor-related ADRs in women, 1 study showed higher digoxin-related mortality risk for women, and 1 study reported a higher risk of mineralocorticoid receptor antagonist-related ADRs in men. No sex differences in ADRs were reported for angiotensin II receptor blockers and ß-blockers. Sex-stratified data were not available for ivabradine. CONCLUSIONS: These results underline the scarcity of ADR data stratified by sex. The study investigators call for a change in standard scientific practice toward reporting of ADR data for women and men separately.