Deep learning-based NT-proBNP prediction from the ECG for risk assessment in the community.

OBJECTIVES: The biomarker N-terminal pro B-type natriuretic peptide (NT-proBNP) has predictive value for identifying individuals at risk for cardiovascular disease (CVD). However, it is not widely used for screening in the general population, potentially due to financial and operational reasons. This study aims to develop a deep-learning model as an efficient means to reliably identify individuals at risk for CVD by predicting serum levels of NT-proBNP from the ECG. METHODS: A deep convolutional neural network was developed using the population-based cohort study Hamburg City Health Study (HCHS, n=8,253, 50.9 % women). External validation was performed in two independent population-based cohorts (SHIP-START, n=3,002, 52.1 % women, and SHIP-TREND, n=3,819, 51.2 % women). Assessment of model performance was conducted using Pearson correlation (R) and area under the receiver operating characteristics curve (AUROC). RESULTS: NT-proBNP was predictable from the ECG (R, 0.566 [HCHS], 0.642 [SHIP-START-0], 0.655 [SHIP-TREND-0]). Across cohorts, predicted NT-proBNP (pNT-proBNP) showed good discriminatory ability for prevalent and incident heart failure (HF) (baseline: AUROC 0.795 [HCHS], 0.816 [SHIP-START-0], 0.783 [SHIP-TREND-0]; first follow-up: 0.669 [SHIP-START-1, 5 years], 0.689 [SHIP-TREND-1, 7.3 years]), comparable to the discriminatory value of measured NT-proBNP. pNT-proBNP also demonstrated comparable results for other incident CVD, including atrial fibrillation, stroke, myocardial infarction, and cardiovascular death. CONCLUSIONS: Deep learning ECG algorithms can predict NT-proBNP concentrations with high diagnostic and predictive value for HF and other major CVD and may be used in the community to identify individuals at risk. Long-standing experience with NT-proBNP can increase acceptance of such deep learning models in clinical practice.

The DZHK research platform: maximisation of scientific value by enabling access to health data and biological samples collected in cardiovascular clinical studies.

The German Centre for Cardiovascular Research (DZHK) is one of the German Centres for Health Research and aims to conduct early and guideline-relevant studies to develop new therapies and diagnostics that impact the lives of people with cardiovascular disease. Therefore, DZHK members designed a collaboratively organised and integrated research platform connecting all sites and partners. The overarching objectives of the research platform are the standardisation of prospective data and biological sample collections among all studies and the development of a sustainable centrally standardised storage in compliance with general legal regulations and the FAIR principles. The main elements of the DZHK infrastructure are web-based and central units for data management, LIMS, IDMS, and transfer office, embedded in a framework consisting of the DZHK Use and Access Policy, and the Ethics and Data Protection Concept. This framework is characterised by a modular design allowing a high standardisation across all studies. For studies that require even tighter criteria additional quality levels are defined. In addition, the Public Open Data strategy is an important focus of DZHK. The DZHK operates as one legal entity holding all rights of data and biological sample usage, according to the DZHK Use and Access Policy. All DZHK studies collect a basic set of data and biosamples, accompanied by specific clinical and imaging data and biobanking. The DZHK infrastructure was constructed by scientists with the focus on the needs of scientists conducting clinical studies. Through this, the DZHK enables the interdisciplinary and multiple use of data and biological samples by scientists inside and outside the DZHK. So far, 27 DZHK studies recruited well over 11,200 participants suffering from major cardiovascular disorders such as myocardial infarction or heart failure. Currently, data and samples of five DZHK studies of the DZHK Heart Bank can be applied for.

Multi-organ assessment in mainly non-hospitalized individuals after SARS-CoV-2 infection: The Hamburg City Health Study COVID programme.

AIMS: Long-term sequelae may occur after SARS-CoV-2 infection. We comprehensively assessed organ-specific functions in individuals after mild to moderate SARS-CoV-2 infection compared with controls from the general population. METHODS AND RESULTS: Four hundred and forty-three mainly non-hospitalized individuals were examined in median 9.6 months after the first positive SARS-CoV-2 test and matched for age, sex, and education with 1328 controls from a population-based German cohort. We assessed pulmonary, cardiac, vascular, renal, and neurological status, as well as patient-related outcomes. Bodyplethysmography documented mildly lower total lung volume (regression coefficient -3.24, adjusted P = 0.014) and higher specific airway resistance (regression coefficient 8.11, adjusted P = 0.001) after SARS-CoV-2 infection. Cardiac assessment revealed slightly lower measures of left (regression coefficient for left ventricular ejection fraction on transthoracic echocardiography -0.93, adjusted P = 0.015) and right ventricular function and higher concentrations of cardiac biomarkers (factor 1.14 for high-sensitivity troponin, 1.41 for N-terminal pro-B-type natriuretic peptide, adjusted P ≤ 0.01) in post-SARS-CoV-2 patients compared with matched controls, but no significant differences in cardiac magnetic resonance imaging findings. Sonographically non-compressible femoral veins, suggesting deep vein thrombosis, were substantially more frequent after SARS-CoV-2 infection (odds ratio 2.68, adjusted P < 0.001). Glomerular filtration rate (regression coefficient -2.35, adjusted P = 0.019) was lower in post-SARS-CoV-2 cases. Relative brain volume, prevalence of cerebral microbleeds, and infarct residuals were similar, while the mean cortical thickness was higher in post-SARS-CoV-2 cases. Cognitive function was not impaired. Similarly, patient-related outcomes did not differ. CONCLUSION: Subjects who apparently recovered from mild to moderate SARS-CoV-2 infection show signs of subclinical multi-organ affection related to pulmonary, cardiac, thrombotic, and renal function without signs of structural brain damage, neurocognitive, or quality-of-life impairment. Respective screening may guide further patient management.

Refined atrial fibrillation screening and cost-effectiveness in the German population.

OBJECTIVE: Little is known on optimal screening population for detecting new atrial fibrillation (AF) in the community. We describe characteristics and estimate cost-effectiveness for a single timepoint electrocardiographic screening. METHODS: We performed a 12-lead ECG in the German population-based Gutenberg Health Study between 2007 and 2012 (n=15 010), mean age 55±11 years, 51% men and collected more than 120 clinical and biomarker variables, including N-terminal pro B-type natriuretic peptide (Nt-proBNP), risk factors, disease symptoms and echocardiographic variables. RESULTS: Of 15 010 individuals, 466 (3.1%) had AF. New AF was found in 32 individuals, 0.2% of the total sample, 0.5% of individuals aged 65-74 years and predominantly men (86%). The classical risk factor burden was high in individuals with new AF. The median estimated stroke risk was 2.2%/year, while risk of developing heart failure was 21% over 10 years. In the 65-74 year age group, the cost per quality-adjusted life-year gained resulting from a single timepoint screening was €30 361. In simulations, the costs were highly sensitive to AF detection rates, proportion of treatment and type of oral anticoagulant. Prescreening by Nt-proBNP measurements was not cost-effective in the current setting. CONCLUSIONS: In our middle-aged population cohort, we identified 0.2% new AF by single timepoint screening. There was a significant estimated risk of stroke and heart failure in these individuals. Cost-effectiveness for screening may be reached in individuals aged 65 years and older. The simple age cut-off is not improved by using Nt-proBNP as a biomarker to guide a screening programme.

Association of glycated hemoglobin A1c levels with cardiovascular outcomes in the general population: results from the BiomarCaRE (Biomarker for Cardiovascular Risk Assessment in Europe) consortium.

BACKGROUND: Biomarkers may contribute to improved cardiovascular risk estimation. Glycated hemoglobin A1c (HbA1c) is used to monitor the quality of diabetes treatment. Its strength of association with cardiovascular outcomes in the general population remains uncertain. This study aims to assess the association of HbA1c with cardiovascular outcomes in the general population. METHODS: Data from six prospective population-based cohort studies across Europe comprising 36,180 participants were analyzed. HbA1c was evaluated in conjunction with classical cardiovascular risk factors (CVRFs) for association with cardiovascular mortality, cardiovascular disease (CVD) incidence, and overall mortality in subjects without diabetes (N = 32,496) and with diabetes (N = 3684). RESULTS: Kaplan-Meier curves showed higher event rates with increasing HbA1c levels (log-rank-test: p < 0.001). Cox regression analysis revealed significant associations between HbA1c (in mmol/mol) in the total study population and the examined outcomes. Thus, a hazard ratio (HR) of 1.16 (95% confidence interval (CI) 1.02-1.31, p = 0.02) for cardiovascular mortality, 1.13 (95% CI 1.03-1.24, p = 0.01) for CVD incidence, and 1.09 (95% CI 1.02-1.17, p = 0.01) for overall mortality was observed per 10 mmol/mol increase in HbA1c. The association with CVD incidence and overall mortality was also observed in study participants without diabetes with increased HbA1c levels (HR 1.12; 95% CI 1.01-1.25, p = 0.04) and HR 1.10; 95% CI 1.01-1.20, p = 0.02) respectively. HbA1c cut-off values of 39.9 mmol/mol (5.8%), 36.6 mmol/mol (5.5%), and 38.8 mmol/mol (5.7%) for cardiovascular mortality, CVD incidence, and overall mortality, showed also an increased risk. CONCLUSIONS: HbA1c is independently associated with cardiovascular mortality, overall mortality and cardiovascular disease in the general European population. A mostly monotonically increasing relationship was observed between HbA1c levels and outcomes. Elevated HbA1c levels were associated with cardiovascular disease incidence and overall mortality in participants without diabetes underlining the importance of HbA1c levels in the overall population.

Natriuretic Peptides and Risk of Type 2 Diabetes: Results From the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Consortium.

OBJECTIVE: Natriuretic peptide (NP) concentrations are increased in cardiovascular diseases (CVDs) but are associated with a lower diabetes risk. We investigated associations of N-terminal pro-B-type NP (NT-proBNP) and midregional proatrial NP (MR-proANP) with incident type 2 diabetes stratified by the presence of CVD. RESEARCH DESIGN AND METHODS: Based on the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Consortium, we included 45,477 participants with NT-proBNP measurements (1,707 developed type 2 diabetes over 6.5 years of median follow-up; among these, 209 had CVD at baseline) and 11,537 participants with MR-proANP measurements (857 developed type 2 diabetes over 13.8 years of median follow-up; among these, 106 had CVD at baseline). The associations were estimated using multivariable Cox regression models. RESULTS: Both NPs were inversely associated with incident type 2 diabetes (hazard ratios [95% CI] per 1-SD increase of log NP: 0.84 [0.79; 0.89] for NT-proBNP and 0.77 [0.71; 0.83] for MR-proANP). The inverse association between NT-proBNP and type 2 diabetes was significant in individuals without CVD but not in individuals with CVD (0.81 [0.76; 0.86] vs. 1.04 [0.90; 1.19]; P multiplicative interaction = 0.001). There was no significant difference in the association of MR-proANP with type 2 diabetes between individuals without and with CVD (0.75 [0.69; 0.82] vs. 0.81 [0.66; 0.99]; P multiplicative interaction = 0.236). CONCLUSIONS: NT-proBNP and MR-proANP are inversely associated with incident type 2 diabetes. However, the inverse association of NT-proBNP seems to be modified by the presence of CVD. Further investigations are warranted to confirm our findings and to investigate the underlying mechanisms.

Target Populations and Treatment Cost for Bempedoic Acid and PCSK9 Inhibitors: A Simulation Study in a Contemporary CAD Cohort.

PURPOSE: The lowered LDL-C treatment goal of the 2019 European Society of Cardiology dyslipidemia guidelines results in a significant increase in the projected need for cost-intensive proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Addition of bempedoic acid (BA) to established oral lipid-lowering medication (LLM) has the potential to enable affordable LDL-C goal attainment, particularly in patients with statin intolerance (SI). The goal of this study was to quantify the target populations for BA and PCSK9 inhibitors as well as the related treatment costs to achieve the LDL-C goal of <55 mg/dL and a ≥50% reduction assuming the addition of BA to LLM. METHODS: This study included 1922 patients with coronary artery disease (CAD) from the contemporary observational cohort study INTERCATH. A Monte Carlo simulation incorporating an algorithm adding sequentially a statin, ezetimibe, optionally BA, and a PCSK9 inhibitor was applied to achieve the LDL-C treatment goal, with consideration of both partial and total SI. Two scenarios were simulated for both a moderate (2% full and 10% partial) and a high (12% full) rate of SI: (1) without BA; and (2) with BA. FINDINGS: Patients' mean age was 69.3 years, and the median baseline LDL-C level was 86.0 mg/dL. The need for a PCSK9 inhibitor would be 41.4% for a moderate rate of SI and 46.1% for a high rate of SI. Addition of BA would: (1) reduce the need for a PCSK9 inhibitor to 25.3% and 29.4%, thus lowering the annual overall treatment cost incurred through PCSK9 inhibitor ± BA per 1 million patients with CAD by 13.3% and 10.5%; (2) lower the cost per prevented event in the entire cohort (-5.0% and -6.3%), although at the price of fewer prevented events (-8.7% and -4.5%); and (3) reduce the cost per prevented event (-6.8% for both rates of SI) while preventing more events (7.6% and 6.9%) in the subpopulation of patients with full SI. IMPLICATIONS: Use of BA is projected to reduce the need for PCSK9 inhibitors as well as the treatment cost for add-on LLM. The subpopulation of patients with full SI might profit particularly.

Critical appraisal of the 2020 ESC guideline recommendations on diagnosis and risk assessment in patients with suspected non-ST-segment elevation acute coronary syndrome.

Multiple new recommendations have been introduced in the 2020 ESC guidelines for the management of acute coronary syndromes with a focus on diagnosis, prognosis, and management of patients presenting without persistent ST-segment elevation. Most recommendations are supported by high-quality scientific evidence. The guidelines provide solutions to overcome obstacles presumed to complicate a convenient interpretation of troponin results such as age-, or sex-specific cutoffs, and to give practical advice to overcome delays of laboratory reporting. However, in some areas, scientific support is less well documented or even missing, and other areas are covered rather by expert opinion or subjective recommendations. We aim to provide a critical appraisal on several recommendations, mainly related to the diagnostic and prognostic assessment, highlighting the discrepancies between Guideline recommendations and the existing scientific evidence.

The need for PCSK9 inhibitors and associated treatment costs according to the 2019 ESC dyslipidaemia guidelines vs. the risk-based allocation algorithm of the 2017 ESC consensus statement: a simulation study in a contemporary CAD cohort.

BACKGROUND: The recently updated European Society of Cardiology (ESC) dyslipidaemia guidelines recommend a lower low-density lipoprotein cholesterol (LDL-C) goal of <55 mg/dL for patients with atherosclerotic cardiovascular disease (ASCVD), with a concomitant Class IA upgrade for proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) for patients not reaching their LDL-C goal under conventional lipid-lowering therapy. AIMS: We aim to quantify the need for PCSK9i and the related costs to achieve the revised LDL-C goal in ASCVD patients compared to former ESC recommendations, in particular the risk-based 2017 ESC consensus update. METHODS AND RESULTS: We included patients with ASCVD from an observational cohort study ongoing since 2015. A Monte Carlo simulation incorporating a treatment algorithm adding sequentially a statin, ezetimibe, and a PCSK9i was applied with consideration of partial and total statin intolerance. The need for PCSK9i was calculated for three different ESC recommendations (2019 guidelines, 2016 guidelines, 2017 consensus update). Preventable events and treatment costs due to PCSK9i were calculated for a range of annual event rates from 2% to 8% and annual treatment costs of ca. 6050 €. We included 1780 patients (mean age 69.5 years). Median LDL-C at baseline was 85.0 mg/dL, with 61% of patients taking lipid-lowering medication. The need for PCSK9i was simulated to be 42.0% (ESC 2019), 31.9% (ESC 2016), and 5.0% (ESC 2017). The LDL-C goals were achieved in 97.9%, 99.1%, and 60.9% of patients, respectively. Annual treatment cost for PCSK9i per 1 000 000 ASCVD patients would be 2.54 billion € (ESC 2019) compared to 0.30 billion € (ESC 2017). Costs per prevented event due to PCSK9i initiation differed widely, e.g. 887 000 € for an event rate of 3% and a treatment goal of <55 mg/dL compared to 205 000 € for an event rate of 7% and risk-based use of PCSK9i. CONCLUSION: The revised LDL-C treatment goals increase the projected need for PCSK9i with a substantial increase in associated treatment cost. An allocation strategy based on residual LDL-C and clinical or angiographic risk factors leads to a more tailored target population for PCSK9i with a reasonable benefit/cost ratio.

Contribution of cystatin C- and creatinine-based definitions of chronic kidney disease to cardiovascular risk assessment in 20 population-based and 3 disease cohorts: the BiomarCaRE project.

BACKGROUND: Chronic kidney disease has emerged as a strong cardiovascular risk factor, and in many current guidelines, it is already considered as a coronary heart disease (CHD) equivalent. Routinely, creatinine has been used as the main marker of renal function, but recently, cystatin C emerged as a more promising marker. The aim of this study was to assess the comparative cardiovascular and mortality risk of chronic kidney disease (CKD) using cystatin C-based and creatinine-based equations of the estimated glomerular filtration rate (eGFR) in participants of population-based and disease cohorts. METHODS: The present study has been conducted within the BiomarCaRE project, with harmonized data from 20 population-based cohorts (n = 76,954) from 6 European countries and 3 cardiovascular disease (CVD) cohorts (n = 4982) from Germany. Cox proportional hazards models were used to assess hazard ratios (HRs) for the various CKD definitions with adverse outcomes and mortality after adjustment for the Systematic COronary Risk Evaluation (SCORE) variables and study center. Main outcome measures were cardiovascular diseases, cardiovascular death, and all-cause mortality. RESULTS: The overall prevalence of CKD stage 3-5 by creatinine- and cystatin C-based eGFR, respectively, was 3.3% and 7.4% in the population-based cohorts and 13.9% and 14.4% in the disease cohorts. CKD was an important independent risk factor for subsequent CVD events and mortality. For example, in the population-based cohorts, the HR for CVD mortality was 1.72 (95% CI 1.53 to 1.92) with creatinine-based CKD and it was 2.14 (95% CI 1.90 to 2.40) based on cystatin-based CKD compared to participants without CKD. In general, the HRs were higher for cystatin C-based CKD compared to creatinine-based CKD, for all three outcomes and risk increased clearly below the conventional threshold for CKD, also in older adults. Net reclassification indices were larger for a cystatin-C based CKD definition. Differences in HRs (between the two CKD measures) in the disease cohorts were less pronounced than in the population-based cohorts. CONCLUSION: CKD is an important risk factor for subsequent CVD events and total mortality. However, point estimates of creatinine- and cystatin C-based CKD differed considerably between low- and high-risk populations. Especially in low-risk settings, the use of cystatin C-based CKD may result in more accurate risk estimates and have better prognostic value.

Assessment of causality of natriuretic peptides and atrial fibrillation and heart failure: a Mendelian randomization study in the FINRISK cohort.

AIMS: Natriuretic peptides are extensively studied biomarkers for atrial fibrillation (AF) and heart failure (HF). Their role in the pathogenesis of both diseases is not entirely understood and previous studies several single-nucleotide polymorphisms (SNPs) at the NPPA-NPPB locus associated with natriuretic peptides have been identified. We investigated the causal relationship between natriuretic peptides and AF as well as HF using a Mendelian randomization approach. METHODS AND RESULTS: N-terminal pro B-type natriuretic peptide (NT-proBNP) (N = 6669), B-type natriuretic peptide (BNP) (N = 6674), and mid-regional pro atrial natriuretic peptide (MR-proANP) (N = 6813) were measured in the FINRISK 1997 cohort. N = 30 common SNPs related to NT-proBNP, BNP, and MR-proANP were selected from studies. We performed six Mendelian randomizations for all three natriuretic peptide biomarkers and for both outcomes, AF and HF, separately. Polygenic risk scores (PRSs) based on multiple SNPs were used as genetic instrumental variable in Mendelian randomizations. Polygenic risk scores were significantly associated with the three natriuretic peptides. Polygenic risk scores were not significantly associated with incident AF nor HF. Most cardiovascular risk factors showed significant confounding percentages, but no association with PRS. A causal relation except for small causal betas is unlikely. CONCLUSION: In our Mendelian randomization approach, we confirmed an association between common genetic variation at the NPPA-NPPB locus and natriuretic peptides. A strong causal relationship between natriuretic peptides and incidence of AF as well as HF at the community-level was ruled out. Therapeutic approaches targeting natriuretic peptides will therefore very likely work through indirect mechanisms.

Decomposing the educational gradient in allostatic load across European populations. What matters the most: differentials in exposure or in susceptibility?

BACKGROUND: We investigate whether socially disadvantaged individuals are more susceptible to the detrimental effects of smoking and alcohol intake on allostatic load (AL), a marker of physiological 'wear and tear', resulting from adaptation to chronic stress. METHODS: In a cross-sectional analysis, 27 019 men and 26 738 women aged 35-74 years were identified from 21 European cohorts in the BiomarCaRE consortium. We defined three educational classes (EDs) according to years of schooling and an AL score as the sum of z-scores of eight selected biomarkers from the cardiovascular, metabolic and inflammatory systems. We used the Oaxaca-Blinder decomposition to disentangle the ED gradient in AL score into the differential exposure (DE, attributable to different distribution of smoking and alcohol intake across EDs) and the differential susceptibility (DS, attributable to a different effect of risk factors on AL across EDs) components. RESULTS: Less-educated men (mean AL difference: 0.68, 95% CI 0.57 to 0.79) and women (1.52, 95% CI 1.40 to 1.64) had higher AL scores. DE accounted for 7% and 6% of the gradient in men and women, respectively. In men, combining smoking and alcohol intake, DS accounted for 42% of the gradient (smoking DS coefficient=0.177, 26% of the gradient; alcohol DS coefficient=0.109; 16%, not statistically significant). DS contribution increased to 69% in metabolic markers. DS estimates were consistent across age groups, irrespective of comorbidities and robust to unmeasured confounding. No DS was observed in women. CONCLUSIONS: In men, a DS mechanism substantially contributes to the educational class gradient in allostatic load.

Temporal trends in the presentation of cardiovascular and cerebrovascular emergencies during the COVID-19 pandemic in Germany: an analysis of health insurance claims.

AIMS: The first reports of declining hospital admissions for major cardiovascular emergencies during the COVID-19 pandemic attracted public attention. However, systematic evidence on this subject is sparse. We aimed to investigate the rate of emergent hospital admissions, subsequent invasive treatments and comorbidities during the COVID-19 pandemic in Germany. METHODS AND RESULTS: This was a retrospective analysis of health insurance claims data from the second largest insurance fund in Germany, BARMER. Patients hospitalized for acute myocardial infarction, acute limb ischemia, aortic rupture, stroke or transient ischemic attack (TIA) between January 1, 2019, and May 31, 2020, were included. Admission rates per 100,000 insured, invasive treatments and comorbidities were compared from January-May 2019 (pre-COVID) to January-May 2020 (COVID). A total of 115,720 hospitalizations were included in the current analysis (51.3% females, mean age 72.9 years). Monthly admission rates declined from 78.6/100,000 insured (pre-COVID) to 70.6/100,000 (COVID). The lowest admission rate was observed in April 2020 (61.6/100,000). Administration rates for ST-segment elevation myocardial infarction (7.3-6.6), non-ST-segment elevation myocardial infarction (16.8-14.6), acute limb ischemia (5.1-4.6), stroke (35.0-32.5) and TIA (13.7-11.9) decreased from pre-COVID to COVID. Baseline comorbidities and the percentage of these patients treated with interventional or open-surgical procedures remained similar over time across all entities. In-hospital mortality in hospitalizations for stroke increased from pre-COVID to COVID (8.5-9.8%). CONCLUSIONS: Admission rates for cardiovascular and cerebrovascular emergencies declined during the pandemic in Germany, while patients' comorbidities and treatment allocations remained unchanged. Further investigation is warranted to identify underlying reasons and potential implications on patients' outcomes.

Screening for transcatheter mitral valve replacement: a decision tree algorithm.

AIMS: The high frequency of screening failure for anatomical reasons in patients with severe mitral valve regurgitation (MR) is a limiting factor in the screening process for transcatheter mitral valve replacement (TMVR). However, data on optimal patient selection are scarce. The present study aimed to develop a screening algorithm based on TMVR screening data. METHODS AND RESULTS: A total of 195 screenings for six different TMVR devices were performed in 94 high-risk patients with severe MR. We compared baseline echocardiographic and multislice computed tomography (MSCT) parameters between the subgroups of patients accepted (N=33) and rejected for TMVR (N=61). Reasons for screening failure were assessed, and a decision tree algorithm was statistically derived. Reasons for screening failure were small LV dimensions (30.6%), small (7.5%) or large (22.5%) annular size, potential risk of LVOT obstruction (22.0%) or mitral annulus calcification (15.6%). A four-step decision tree algorithm to assess TMVR eligibility was developed resulting in an AUC of 0.80 (95% CI: 0.71, 0.89, p<0.0001). CONCLUSIONS: This study presents the first screening algorithm to assess anatomical eligibility for TMVR in patients with severe MR, based on simple MSCT criteria. Given the high rate of TMVR screening failure, this algorithm may facilitate the identification of potential TMVR candidates.

Association of Circulating Metabolites With Risk of Coronary Heart Disease in a European Population: Results From the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Consortium.

Importance: Risk stratification for coronary heart disease (CHD) remains challenging because of the complex causative mechanism of the disease. Metabolomic profiling offers the potential to detect new biomarkers and improve CHD risk assessment. Objective: To evaluate the association between circulating metabolites and incident CHD in a large European cohort. Design, Setting, and Participants: This population-based study used the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) case-cohort to measure circulating metabolites using a targeted approach in serum samples from 10 741 individuals without prevalent CHD. The cohort consisted of a weighted, random subcohort of the original cohort of more than 70 000 individuals. The case-cohort design was applied to 6 European cohorts: FINRISK97 (Finland), Monitoring of Trends and Determinants in Cardiovascular Diseases/Cooperative Health Research in the Region of Augsburg (MONICA/KORA; Germany), MONICA-Brianza and Moli-sani (Italy), DanMONICA (Denmark), and the Scottish Heart Health Extended Cohort (United Kingdom). Main Outcomes and Measures: Associations with time to CHD onset were assessed individually by applying weighted and adjusted Cox proportional hazard models. The association of metabolites with CHD onset was examined by C indices. Results: In 10 741 individuals (4157 women [38.7%]; median [interquartile range] age, 56.5 [49.2-62.2] years), 2166 incident CHD events (20.2%) occurred over a median (interquartile range) follow-up time of 9.2 (4.5-15.0) years. Among the 141 metabolites analyzed, 24 were significantly associated with incident CHD at a nominal P value of .05, including phosphatidylcholines (PCs), lysoPCs, amino acids, and sphingolipids. Five PCs remained significant after correction for multiple testing: acyl-alkyl-PC C40:6 (hazard ratio [HR], 1.13 [95% CI, 1.07-1.18]), diacyl-PC C40:6 (HR, 1.10 [95% CI, 1.04-1.15]), acyl-alkyl-PC C38:6 (HR, 1.11 [95% CI, 1.05-1.16]), diacyl-PC C38:6 (HR, 1.09 [95% CI, 1.04-1.14]) and diacyl-PC C38:5 (HR, 1.10 [95% CI, 1.05-1.16]). Lower levels of these metabolites were associated with increased risk of incident CHD. The strength of the associations competes with those of classic risk factors (C statistics: acyl-alkyl-PC C40:6, 0.756 [95% CI, 0.738-0.774], diacyl-PC C40:6, 0.754 [95% CI, 0.736-0.772], acyl-alkyl-PC C38:6, 0.755 [95% CI, 0.736-0.773], diacyl-PC C38:6, 0.754 [95% CI, 0.736-0.772]), diacyl-PC C38:5, 0.754 [95% CI, 0.736-0.772]). Adding metabolites to a base risk model including classic risk factors high-sensitivity C-reactive protein and high-sensitivity troponin I did not improve discrimination by C statistics. Conclusions and Relevance: Five PCs were significantly associated with increased risk of incident CHD and showed comparable discrimination with individual classic risk factors. Although these metabolites do not improve CHD risk assessment beyond that of classic risk factors, these findings hold promise for an improved understanding of the pathophysiology of CHD.

Systematic assessment of decision-analytic models evaluating diagnostic tests for acute myocardial infarction based on cardiac troponin assays.

INTRODUCTION: Despite the emphasis on the clinical importance of cardiac troponin assays (cTn), there are insufficient cost-effectiveness comparisons of various troponin test protocols for the diagnosis of myocardial infarction (MI). Therefore, the purpose of the review was to identify and systematically assess published economic evaluations using decision-analytic models for diagnostic testing strategies based on cTn and to make recommendations for the development of future models. AREAS COVERED: MEDLINE, Science Direct, Cochrane Database, CRD Database, and gray literature were screened for full economic evaluation studies with relevant clinical outcomes over a defined time horizon addressing a population with suspected MI and comparison of different diagnostic test strategies. Standardized forms for data extraction and evidence tables were used for the summary of study design, methodological framework and data sources. Studies were assessed for quality using the CHEERS and the BMJ checklists. EXPERT COMMENTARY: Although there are 11 identified studies and several well-designed models, there remains a need for decision-analytic models including differential diagnosis for acute MI, different health facility configurations, clinician preferences, and behavioral components, and in the top of the subgroup analyses additional important personalized medicine aspects.

Relations of Sex to Diagnosis and Outcomes in Acute Coronary Syndrome.

BACKGROUND: The atypical presentation of women with acute coronary syndrome (ACS) has been related to delayed diagnosis and treatment, which may explain worse outcome compared with men. METHODS AND RESULTS: We analyzed pooled data of 2520 patients of 2 prospective cohorts in terms of differences in presentation and management of women and men suggestive of ACS. Using logistic regression, we established 2 diagnostic models and tested their diagnostic performance in both sexes separately. Sex-specific differences in management of patients with ACS were ascertained and a 2-year follow-up was performed. Women were older than men (median 67 versus 61 years, P=0.001), had more often dyspnea (22% versus 18%, P=0.024), nausea or vomiting (26% versus 16%, P=0.001) and radiating chest pain (47% versus 40%, P=0.001). Classical risk factors (smoking, diabetes mellitus, dyslipidemia or known coronary artery disease) were less frequent in women. Diagnostic models showed no significant sex-related differences in diagnostic performance in a "first contact" setting (medical history and symptoms) or after "complete triage" (including ECG and biomarkers). Women with ACS underwent coronary angiography (73.8% versus 84.3%, P<0.001) and revascularization (53.8% versus 70.1%, P<0.001) less frequently. Two-year incidence of myocardial infarction and death was similar in both sexes, but revascularization and cardiac rehospitalization were more frequent in men. CONCLUSIONS: In a large cohort of patients with suspected ACS, sex differences in clinical presentation did not impair diagnostic accuracy. Two-year outcomes were comparable. Our findings suggest a benefit of chest pain units to minimize sex differences in ACS management and prognosis. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT02355457 (BACC), NCT03227159 (stenoCardia).

Sex Differences and Similarities in Atrial Fibrillation Epidemiology, Risk Factors, and Mortality in Community Cohorts: Results From the BiomarCaRE Consortium (Biomarker for Cardiovascular Risk Assessment in Europe).

BACKGROUND: Atrial fibrillation (AF) is a common cardiac disease in aging populations with high comorbidity and mortality. Sex differences in AF epidemiology are insufficiently understood. METHODS: In N=79 793 individuals without AF diagnosis at baseline (median age, 49.6 years; age range, 24.1-97.6 years; 51.7% women) from 4 community-based European studies (FINRISK, DanMONICA, Moli-sani Northern Sweden) of the BiomarCaRE consortium (Biomarker for Cardiovascular Risk Assessment in Europe), we examined AF incidence, its association with mortality, common risk factors, biomarkers, and prevalent cardiovascular disease, and their attributable risk by sex. Median follow-up time was 12.6 (to a maximum of 28.2) years. RESULTS: Fewer AF cases were observed in women (N=1796; 4.4%), than in men (N=2465; 6.4%). Cardiovascular risk factor distribution and lipid profile at baseline were less beneficial in men than in women, and cardiovascular disease was more prevalent in men. Cumulative incidence increased markedly after the age of 50 years in men and after 60 years in women. The lifetime risk was similar (>30%) for both sexes. Subjects with incident AF had a 3.5-fold risk of death in comparison with those without AF. Multivariable-adjusted models showed sex differences for the association of body mass index and AF (hazard ratio per standard deviation increase, 1.18; 95% confidence interval [CI], 1.12-1.23 in women versus 1.31; 95% CI 1.25-1.38 in men; interaction P value of 0.001). Total cholesterol was inversely associated with incident AF with a greater risk reduction in women (hazard ratio per SD, 0.86; 95% CI, 0.81-0.90 versus 0.92; 95% CI, 0.88-0.97 in men; interaction P value of 0.023). No sex differences were seen for C-reactive protein and N-terminal pro B-type natriuretic peptide. The population-attributable risk of all risk factors combined was 41.9% in women and 46.0% in men. About 20% of the risk was observed for body mass index. CONCLUSIONS: Lifetime risk of AF was high, and AF was strongly associated with increased mortality both in women and men. Body mass index explained the largest proportion of AF risk. Observed sex differences in the association of body mass index and total cholesterol with AF need to be evaluated for underlying pathophysiology and relevance to sex-specific prevention strategies.

Acute versus Chronic Myocardial Infarction: Diagnostic Accuracy of Quantitative Native T1 and T2 Mapping versus Assessment of Edema on Standard T2-weighted Cardiovascular MR Images for Differentiation.

Purpose To analyze the diagnostic accuracy of native T1 and T2 mapping compared with visual and quantitative assessment of edema on T2-weighted cardiac magnetic resonance (MR) images to differentiate between acute and chronic myocardial infarction. Materials and Methods This study had institutional ethics committee approval. Written informed consent was obtained from 67 consecutive patients (57 years ± 12; 78% men) with a first acute myocardial infarction, who were prospectively enrolled between April 2011 and June 2015. Four serial 1.5-T MR imaging examinations were performed at 8 days ± 5, 7 weeks ± 2, 3 months ± 0.5, and 6 months ± 1.4 after infarction and included T2-weighted, native T1/T2 mapping, and late gadolinium enhancement MR imaging. Complete follow-up data were obtained in 42 patients. Regional native T1/T2 relaxation time, T2-weighted ratio, and extracellular volume were serially measured in infarcted and remote myocardium. Receiver operating characteristic (ROC) analysis was used to determine the diagnostic accuracy of the MR imaging parameters for discriminating between acute and chronic myocardial infarction. Results Native T1 of infarcted myocardium decreased from 1286 msec ± 99 at baseline to 1077 msec ± 50 at 6 months (P < .0001), whereas T2 decreased from 84 msec ± 10 to 58 msec ± 4 (P < .0001). The T2-weighted ratio decreased from 4.1 ± 1.0 to 2.4 ± 0.6 (P < .0001). Of all the MR imaging parameters obtained, native T1 and T2 yielded the best areas under the ROC curve (AUCs) of 0.975 and 0.979, respectively, for differentiating between acute and chronic myocardial infarction. Visual analysis of the presence of edema at standard T2-weighted cardiac MR imaging resulted in an inferior AUC of 0.863 (P < .01). Conclusion Native T1 and T2 of infarcted myocardium are excellent discriminators between acute and chronic myocardial infarction and are superior to all other MR imaging parameters. Online supplemental material is available for this article.