The HEARTS partner forum-supporting implementation of HEARTS to treat and control hypertension.

Cardiovascular diseases (CVD), principally ischemic heart disease (IHD) and stroke, are the leading causes of death (18. 6 million deaths annually) and disability (393 million disability-adjusted life-years lost annually), worldwide. High blood pressure is the most important preventable risk factor for CVD and deaths, worldwide (10.8 million deaths annually). In 2016, the World Health Organization (WHO) and the United States Centers for Disease Control (CDC) launched the Global Hearts initiative to support governments in their quest to prevent and control CVD. HEARTS is the core technical package of the initiative and takes a public health approach to treating hypertension and other CVD risk factors at the primary health care level. The HEARTS Partner Forum, led by WHO, brings together the following 11 partner organizations: American Heart Association (AHA), Center for Chronic Disease Control (CCDC), International Society of Hypertension (ISH), International Society of Nephrology (ISN), Pan American Health Organization (PAHO), Resolve to Save Lives (RTSL), US CDC, World Hypertension League (WHL), World Heart Federation (WHF) and World Stroke Organization (WSO). The partners support countries in their implementation of the HEARTS technical package in various ways, including providing technical expertise, catalytic funding, capacity building and evidence generation and dissemination. HEARTS has demonstrated the feasibility and acceptability of a public health approach, with more than seven million people already on treatment for hypertension using a simple, algorithmic HEARTS approach. Additionally, HEARTS has demonstrated the feasibility of using hypertension as a pathfinder to universal health coverage and should be a key intervention of all basic benefit packages. The partner forum continues to find ways to expand support and reinvigorate enthusiasm and attention on preventing CVD. Proposed future HEARTS Partner Forum activities are related to more concrete information sharing between partners and among countries, expanded areas of partner synergy, support for implementation, capacity building, and advocacy with country ministries of health, professional societies, academy and civil societies organizations. Advancing toward the shared goals of the HEARTS partners will require a more formal, structured approach to the forum and include goals, targets and published reports. In this way, the HEARTS Partner Forum will mirror successful global partnerships on communicable diseases and assist countries in reducing CVD mortality and achieving global sustainable development goals (SDGs).

Plasma Proteomic Patterns Show Sex Differences in Early Concentric Left Ventricular Remodeling.

BACKGROUND: Concentric remodeling (cRM) can precede heart failure with preserved ejection fraction (HFpEF), a condition prevalent in women. METHODS: Patients (n=60 593, 54.2% women) visiting outpatient clinics of Cardiology Centers of the Netherlands were analyzed for cRM, HFpEF development, and mortality risk. We studied risk factors for relative wall thickness both sex-stratified and in women and men combined. Biomarker profiling was performed (4534 plasma proteins) in a substudy involving 557 patients (65.4% women) to identify pathways involved in cRM. RESULTS: cRM was present in 23.5% of women and 27.6% of men and associated with developing HFpEF (HR, 2.15 [95% CI, 1.51-2.99]) and mortality risk (HR, 1.09 [95% CI, 1.00-1.19]) in both sexes. Age, heart rate, and hypertension were statistically significantly stronger risk factors for relative wall thickness in women than men. Higher circulating levels of IFNA5 (interferon alpha-5) were associated with higher relative wall thickness in women only. Pathway analysis revealed differential pathway activation by sex and increased expression of inflammatory pathways in women. CONCLUSIONS: cRM is prevalent in approximately 1 in 4 women and men visiting outpatient cardiology clinics and associated with HFpEF development and mortality risk in both sexes. Known risk factors for cRM were more strongly associated in women than men. Proteomic analysis revealed inflammatory pathway activation in women, with a central role for IFNA5. Differential biologic pathway activation by sex in cRM may contribute to the female predominance of HFpEF and holds promise for identification of new therapeutic avenues for prevention and treatment of HFpEF. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT001747.

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.

[Coronary calcium CT-scanning advisable in patients with a high cardiovascular risk: refining cardiovascular risk in primary prevention]. / Wanneer is de coronaire calciumscore zinvol?

Currently, risk prediction models like SCORE are used for decision making in the primary prevention of cardiovascular disease. The external validity of these models is questionable since they give rise to overtreatment with statins or antihypertensive drugs. Detailed individual risk assessment may reduce this drawback and will increase cost effectiveness. The CT derived coronary calcium score, in asymptomatic patients, was shown to be more accurate than the current prediction models. A coronary calcium score of zero reclassifies a significant number of individuals to a lower risk group and subsequently prevent overtreatment. Using this strategy, it can be anticipated that the Dutch healthcare costs can be reduced by at least 15 million Euro per year.

Functional stress imaging to predict abnormal coronary fractional flow reserve: the PACIFIC 2 study.

AIMS: The diagnostic performance of non-invasive imaging in patients with prior coronary artery disease (CAD) has not been tested in prospective head-to-head comparative studies. The aim of this study was to compare the diagnostic performance of qualitative single-photon emission computed tomography (SPECT), quantitative positron emission tomography (PET), and qualitative magnetic resonance imaging (MRI) in patients with a prior myocardial infarction (MI) or percutaneous coronary intervention (PCI). METHODS AND RESULTS: In this prospective clinical study, all patients with prior MI and/or PCI and new symptoms of ischaemic CAD underwent 99mTc-tetrofosmin SPECT, [15O]H2O PET, and MRI, followed by invasive coronary angiography with fractional flow reserve (FFR) in all coronary arteries. All modalities were interpreted by core laboratories. Haemodynamically significant CAD was defined by at least one coronary artery with an FFR ≤0.80. Among the 189 enrolled patients, 63% had significant CAD. Sensitivity was 67% (95% confidence interval 58-76%) for SPECT, 81% (72-87%) for PET, and 66% (56-75%) for MRI. Specificity was 61% (48-72%) for SPECT, 65% (53-76%) for PET, and 62% (49-74%) for MRI. Sensitivity of PET was higher than SPECT (P = 0.016) and MRI (P = 0.014), whereas specificity did not differ among the modalities. Diagnostic accuracy for PET (75%, 68-81%) did not statistically differ from SPECT (65%, 58-72%, P = 0.03) and MRI (64%, 57-72%, P = 0.052). Using FFR < 0.75 as a reference, accuracies increased to 69% (SPECT), 79% (PET), and 71% (MRI). CONCLUSION: In this prospective head-to-head comparative study, SPECT, PET, and MRI did not show a significantly different accuracy for diagnosing FFR defined significant CAD in patients with prior PCI and/or MI. Overall diagnostic performances, however, were discouraging and the additive value of non-invasive imaging in this high-risk population is questionable.

Statins are associated with a large reduction in all-cause mortality in women from a cardiac outpatient population.

OBJECTIVES: Uncertainty about the benefit of (high-intensity) statins for women remains due to under-representation of women in primary prevention trials and scarcity of sex-stratified data. This study evaluates the sex-specific relation between statin treatment and survival and the additional benefit of high-intensity statins. METHODS: Electronic health record data from 47 801 patients (17 008 statin users and 30 793 non-users) without prior cardiovascular disease were extracted from thirteen Dutch outpatient cardiology clinics. Patients prescribed statins at baseline were propensity-score matched to those eligible for statin therapy (low-density lipoprotein >2.5 mmol/L) without a statin prescription. Statins were divided into low-intensity and high-intensity according to Dutch guidelines. Mortality data were obtained via linkage to the national mortality registry. Cox regression was used to evaluate the relationship between statin prescription and intensity and all-cause and cardiovascular mortality. RESULTS: Propensity score matching created a cohort of 8631 statin users and 8631 non-users. 35% of women and 28% of men received a low-intensity statin. The beneficial effect of statins on both all-cause and cardiovascular mortality was stronger in women (HR 0.66, 95% CI 0.58 to 0.74 and HR 0.55, 95% CI 0.39 to 0.71, respectively) than in men (HR 0.89, 95% CI 0.81 to 0.95 and HR 0.93, 95% CI 0.77 to 1.08, respectively). High-intensity statins conferred modest protection against all-cause mortality (HR 0.94, 95% CI 0.88 to 1.00) and cardiovascular mortality (HR 0.86, 95% CI 0.74 to 0.98) in both sexes. CONCLUSIONS: The protective effect of primary prevention statins was stronger in women than men for both all-cause and cardiovascular mortality. High-intensity statins conferred a modest additional benefit in both sexes. Statins seem to be effective regardless of treatment intensity, especially in women.

The HFA-PEFF score identifies 'early-HFpEF' phenogroups associated with distinct biomarker profiles.

AIMS: The HFA-PEFF score was developed to optimize diagnosis and to aid in early recognition of heart failure (HF) with preserved ejection fraction (HFpEF) in patients who present with HF-like symptoms. Recognizing early-HFpEF phenogroups is essential to better understand progression towards overt HFpEF and pave the way for early intervention and treatment. Whether the HFA-PEFF domain scores can identify 'early-HFpEF' phenogroups remains unknown. The aims of this pilot study are to (i) identify distinct phenogroups by cluster analysis of HFA-PEFF domain scores in subjects that present with HF-like symptoms and (ii) study whether these phenogroups may be associated with distinct blood proteome profiles. METHODS AND RESULTS: Subjects referred to the Cardiology Centers of the Netherlands, location Utrecht, with non-acute possibly cardiac-related symptoms (such as dyspnoea or fatigue) were prospectively enrolled in the HELPFul cohort (N = 507) and were included in the current analysis. Inclusion criteria for this study were (i) age ≥ 45 years and (ii) a left ventricular ejection fraction (LVEF) ≥ 50%, in the absence of a history of HF, coronary artery disease, congenital heart disease, or any previous cardiac interventions. Multinominal-based clustering with latent class model using the HFA-PEFF domain scores (functional, structural, and biomarker scores) as input was used to detect distinct phenotypic clusters. For each bootstrapping run, the 92 Olink proteins were analysed for their association with the identified phenogroups. Four distinct phenogroups were identified in the current analysis (validated by bootstrapping 1000×): (i) no left ventricular diastolic dysfunction (no LVDD, N = 102); (ii) LVDD with functional left ventricular (LV) abnormalities (N = 204); (iii) LVDD with functional and structural LV abnormalities (N = 204); and (iv) LVDD with functional and structural LV abnormalities and elevated BNP (N = 107). The HFA-PEFF total score risk categories significantly differed between the phenogroups (P < 0.001), with an increase of the HFA-PEFF score from Phenogroup 1 to 4 (low/intermediate/high HFA-PEFF risk score: Phenogroup 1: 88%/12%/0%; Phenogroup 2: 9%/91%/0%; Phenogroup 3: 0%/92%/8%; Phenogroup 4: 5%/83%/12%). Thirty-two out of the 92 Olink protein biomarkers significantly differed among the phenogroups. The top eight biomarkers-N-terminal prohormone brain natriuretic peptide, growth differentiation factor-15, matrix metalloproteinase-2, osteoprotegerin, tissue inhibitor of metalloproteinase-4, chitinase-3-like protein 1, insulin-like growth factor-binding protein 2, and insulin-like growth factor-binding protein 7-are mainly involved in inflammation and extracellular matrix remodelling, which are currently proposed key processes in HFpEF pathophysiology. CONCLUSIONS: This study identified distinct phenogroups by using the HFA-PEFF domain scores in ambulant subjects referred for HF-like symptoms. The newly identified phenogroups accompanied by their circulating biomarkers profile might aid in a better understanding of the pathophysiological processes involved during the early stages of the HFpEF syndrome.

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.

Outcomes in patients with a first episode of chest pain undergoing early coronary CT imaging.

OBJECTIVES: To investigate the impact of a CT-first strategy on all-cause and cardiovascular mortality in patients presenting with chest pain in outpatient cardiology clinics. METHODS: Patients with a first presentation of suspected angina pectoris were identified and their data linked to the registrations of Statistics Netherlands for information on mortality. The linked database consisted of 33 068 patients. CT-first patients were defined as patients with a CT calcium score and coronary CT angiography, within 6 weeks after their initial visit. Propensity score matching (1:5) was used to match patients with and without a CT-first strategy. After matching, 12 545 patients were included of which 2308 CT-first patients and 10 237 patients that underwent usual care. RESULTS: Mean age was 57 years, 56.3% were women and median follow-up was 4.9 years. All-cause mortality was significantly lower in CT-first patients (n=43, 1.9%) compared with patients without CT (n=363, 3.5%) (HR: 0.51, 95% CI 0.37 to 0.70). Furthermore, CT-first patients were more likely to receive cardiovascular preventative and antianginal medication (aspirin: 44.9% vs 27.1%, statins: 48.7% vs 30.3%, beta-blockers: 37.8% vs 25.5%, in CT-first and without CT-first patients, respectively) and to undergo downstream diagnostics and interventions (coronary interventions: 8.5% vs 5.7%, coronary angiography: 16.2% vs 10.6% in CT-first and without CT-first patients, respectively). CONCLUSIONS: In a real-world regular care database, a CT-first strategy in patients suspected of angina pectoris was associated with a lowering of all-cause mortality.

Deep neural networks reveal novel sex-specific electrocardiographic features relevant for mortality risk.

Aims: Incorporation of sex in study design can lead to discoveries in medical research. Deep neural networks (DNNs) accurately predict sex based on the electrocardiogram (ECG) and we hypothesized that misclassification of sex is an important predictor for mortality. Therefore, we first developed and validated a DNN that classified sex based on the ECG and investigated the outcome. Second, we studied ECG drivers of DNN-classified sex and mortality. Methods and results: A DNN was trained to classify sex based on 131 673 normal ECGs. The algorithm was validated on internal (68 500 ECGs) and external data sets (3303 and 4457 ECGs). The survival of sex (mis)classified groups was investigated using time-to-event analysis and sex-stratified mediation analysis of ECG features. The DNN successfully distinguished female from male ECGs {internal validation: area under the curve (AUC) 0.96 [95% confidence interval (CI): 0.96, 0.97]; external validations: AUC 0.89 (95% CI: 0.88, 0.90), 0.94 (95% CI: 0.93, 0.94)}. Sex-misclassified individuals (11%) had a 1.4 times higher mortality risk compared with correctly classified peers. The ventricular rate was the strongest mediating ECG variable (41%, 95% CI: 31%, 56%) in males, while the maximum amplitude of the ST segment was strongest in females (18%, 95% CI: 11%, 39%). Short QRS duration was associated with higher mortality risk. Conclusion: Deep neural networks accurately classify sex based on ECGs. While the proportion of ECG-based sex misclassifications is low, it is an interesting biomarker. Investigation of the causal pathway between misclassification and mortality uncovered new ECG features that might be associated with mortality. Increased emphasis on sex as a biological variable in artificial intelligence is warranted.

A media intervention applying debunking versus non-debunking content to combat vaccine misinformation in elderly in the Netherlands: A digital randomised trial.

BACKGROUND: As several COVID-19 vaccines are rolled-out globally, it has become important to develop an effective strategy for vaccine acceptance, especially in high-risk groups, such as elderly. Vaccine misconception was declared by WHO as one of the top 10 health issues in 2019. Here we test the effectiveness of applying debunking to combat vaccine misinformation, and reduce vaccine hesitancy. METHODS: Participants were recruited via a daily news show on Dutch Television, targeted to elderly viewers. The study was conducted in 980 elderly citizens during the October 2020 National Influenza Vaccination Campaign. Borrowing from the recent literature in behavioural science and psychology we conducted a two-arm randomized blinded parallel study, in which participants were allocated to exposure to a video containing social norms, vaccine information plus debunking of vaccination myths (intervention group, n = 505) or a video only containing vaccine information plus social norm (control group, n = 475). Participants who viewed either of the video's and completed both a pre- and post-intervention survey on vaccination trust and knowledge, were included in the analysis. The main outcomes of this study were improvement on vaccine knowledge and awareness. FINDINGS: Participants were recruited from the 13th of October 2020 till the 16th of October 2020 and could immediately participate in the pre-intervention survey. Subsequently, eligible participants were randomly assigned to an interventional video and the follow-up survey, distributed through email on the 18th of October 2020, and available for participation till the 24th of October 2020. We found that exposure to the video with addition of debunking strategies on top of social norm modelling and information resulted in substantially stronger rejection of vaccination misconceptions, including the belief that: (1) vaccinations can cause Autism Spectrum Disorders; (2) vaccinations weaken the immune system; (3) influenza vaccination would hamper the COVID-19 vaccine efficacy. Additionally, we observed that exposure to debunking in the intervention resulted in enhanced trust in government. INTERPRETATION: Utilizing debunking in media campaigns on top of vaccine information and social norm modeling is an effective means to combat misinformation and distrust associated with vaccination in elderly, and could help maximize grounds for the acceptance of vaccines, including the COVID-19 vaccines. FUNDING: Dutch Influenza Foundation.

Routine clinical care data from thirteen cardiac outpatient clinics: design of the Cardiology Centers of the Netherlands (CCN) database.

BACKGROUND: Despite the increasing availability of clinical data due to the digitalisation of healthcare systems, data often remain inaccessible due to the diversity of data collection systems. In the Netherlands, Cardiology Centers of the Netherlands (CCN) introduced "one-stop shop" diagnostic clinics for patients suspected of cardiac disease by their general practitioner. All CCN clinics use the same data collection system and standardised protocol, creating a large regular care database. This database can be used to describe referral practices, evaluate risk factors for cardiovascular disease (CVD) in important patient subgroups, and develop prediction models for use in daily care. CONSTRUCTION AND CONTENT: The current database contains data on all patients who underwent a cardiac workup in one of the 13 CCN clinics between 2007 and February 2018 (n = 109,151, 51.9% women). Data were pseudonymised and contain information on anthropometrics, cardiac symptoms, risk factors, comorbidities, cardiovascular and family history, standard blood laboratory measurements, transthoracic echocardiography, electrocardiography in rest and during exercise, and medication use. Clinical follow-up is based on medical need and consisted of either a repeat visit at CCN (43.8%) or referral for an external procedure in a hospital (16.5%). Passive follow-up via linkage to national mortality registers is available for 95% of the database. UTILITY AND DISCUSSION: The CCN database provides a strong base for research into historically underrepresented patient groups due to the large number of patients and the lack of in- and exclusion criteria. It also enables the development of artificial intelligence-based decision support tools. Its contemporary nature allows for comparison of daily care with the current guidelines and protocols. Missing data is an inherent limitation, as the cardiologist could deviate from standardised protocols when clinically indicated. CONCLUSION: The CCN database offers the opportunity to conduct research in a unique population referred from the general practitioner to the cardiologist for diagnostic workup. This, in combination with its large size, the representation of historically underrepresented patient groups and contemporary nature makes it a valuable tool for expanding our knowledge of cardiovascular diseases. TRIAL REGISTRATION: Not applicable.

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.