Microstructural and Microvascular Phenotype of Sarcomere Mutation Carriers and Overt Hypertrophic Cardiomyopathy.

BACKGROUND: In hypertrophic cardiomyopathy (HCM), myocyte disarray and microvascular disease (MVD) have been implicated in adverse events, and recent evidence suggests that these may occur early. As novel therapy provides promise for disease modification, detection of phenotype development is an emerging priority. To evaluate their utility as early and disease-specific biomarkers, we measured myocardial microstructure and MVD in 3 HCM groups-overt, either genotype-positive (G+LVH+) or genotype-negative (G-LVH+), and subclinical (G+LVH-) HCM-exploring relationships with electrical changes and genetic substrate. METHODS: This was a multicenter collaboration to study 206 subjects: 101 patients with overt HCM (51 G+LVH+ and 50 G-LVH+), 77 patients with G+LVH-, and 28 matched healthy volunteers. All underwent 12-lead ECG, quantitative perfusion cardiac magnetic resonance imaging (measuring myocardial blood flow, myocardial perfusion reserve, and perfusion defects), and cardiac diffusion tensor imaging measuring fractional anisotropy (lower values expected with more disarray), mean diffusivity (reflecting myocyte packing/interstitial expansion), and second eigenvector angle (measuring sheetlet orientation). RESULTS: Compared with healthy volunteers, patients with overt HCM had evidence of altered microstructure (lower fractional anisotropy, higher mean diffusivity, and higher second eigenvector angle; all P<0.001) and MVD (lower stress myocardial blood flow and myocardial perfusion reserve; both P<0.001). Patients with G-LVH+ were similar to those with G+LVH+ but had elevated second eigenvector angle (P<0.001 after adjustment for left ventricular hypertrophy and fibrosis). In overt disease, perfusion defects were found in all G+ but not all G- patients (100% [51/51] versus 82% [41/50]; P=0.001). Patients with G+LVH- compared with healthy volunteers similarly had altered microstructure, although to a lesser extent (all diffusion tensor imaging parameters; P<0.001), and MVD (reduced stress myocardial blood flow [P=0.015] with perfusion defects in 28% versus 0 healthy volunteers [P=0.002]). Disarray and MVD were independently associated with pathological electrocardiographic abnormalities in both overt and subclinical disease after adjustment for fibrosis and left ventricular hypertrophy (overt: fractional anisotropy: odds ratio for an abnormal ECG, 3.3, P=0.01; stress myocardial blood flow: odds ratio, 2.8, P=0.015; subclinical: fractional anisotropy odds ratio, 4.0, P=0.001; myocardial perfusion reserve odds ratio, 2.2, P=0.049). CONCLUSIONS: Microstructural alteration and MVD occur in overt HCM and are different in G+ and G- patients. Both also occur in the absence of hypertrophy in sarcomeric mutation carriers, in whom changes are associated with electrocardiographic abnormalities. Measurable changes in myocardial microstructure and microvascular function are early-phenotype biomarkers in the emerging era of disease-modifying therapy.

Myocardial Involvement After Hospitalization for COVID-19 Complicated by Troponin Elevation: A Prospective, Multicenter, Observational Study.

BACKGROUND: Acute myocardial injury in hospitalized patients with coronavirus disease 2019 (COVID-19) has a poor prognosis. Its associations and pathogenesis are unclear. Our aim was to assess the presence, nature, and extent of myocardial damage in hospitalized patients with troponin elevation. METHODS: Across 25 hospitals in the United Kingdom, 342 patients with COVID-19 and an elevated troponin level (COVID+/troponin+) were enrolled between June 2020 and March 2021 and had a magnetic resonance imaging scan within 28 days of discharge. Two prospective control groups were recruited, comprising 64 patients with COVID-19 and normal troponin levels (COVID+/troponin-) and 113 patients without COVID-19 or elevated troponin level matched by age and cardiovascular comorbidities (COVID-/comorbidity+). Regression modeling was performed to identify predictors of major adverse cardiovascular events at 12 months. RESULTS: Of the 519 included patients, 356 (69%) were men, with a median (interquartile range) age of 61.0 years (53.8, 68.8). The frequency of any heart abnormality, defined as left or right ventricular impairment, scar, or pericardial disease, was 2-fold greater in cases (61% [207/342]) compared with controls (36% [COVID+/troponin-] versus 31% [COVID-/comorbidity+]; P<0.001 for both). More cases than controls had ventricular impairment (17.2% versus 3.1% and 7.1%) or scar (42% versus 7% and 23%; P<0.001 for both). The myocardial injury pattern was different, with cases more likely than controls to have infarction (13% versus 2% and 7%; P<0.01) or microinfarction (9% versus 0% and 1%; P<0.001), but there was no difference in nonischemic scar (13% versus 5% and 14%; P=0.10). Using the Lake Louise magnetic resonance imaging criteria, the prevalence of probable recent myocarditis was 6.7% (23/342) in cases compared with 1.7% (2/113) in controls without COVID-19 (P=0.045). During follow-up, 4 patients died and 34 experienced a subsequent major adverse cardiovascular event (10.2%), which was similar to controls (6.1%; P=0.70). Myocardial scar, but not previous COVID-19 infection or troponin, was an independent predictor of major adverse cardiovascular events (odds ratio, 2.25 [95% CI, 1.12-4.57]; P=0.02). CONCLUSIONS: Compared with contemporary controls, patients with COVID-19 and elevated cardiac troponin level have more ventricular impairment and myocardial scar in early convalescence. However, the proportion with myocarditis was low and scar pathogenesis was diverse, including a newly described pattern of microinfarction. REGISTRATION: URL: https://www.isrctn.com; Unique identifier: 58667920.

Consumer-Led Screening for Atrial Fibrillation: Frontier Review of the AF-SCREEN International Collaboration.

The technological evolution and widespread availability of wearables and handheld ECG devices capable of screening for atrial fibrillation (AF), and their promotion directly to consumers, has focused attention of health care professionals and patient organizations on consumer-led AF screening. In this Frontiers review, members of the AF-SCREEN International Collaboration provide a critical appraisal of this rapidly evolving field to increase awareness of the complexities and uncertainties surrounding consumer-led AF screening. Although there are numerous commercially available devices directly marketed to consumers for AF monitoring and identification of unrecognized AF, health care professional-led randomized controlled studies using multiple ECG recordings or continuous ECG monitoring to detect AF have failed to demonstrate a significant reduction in stroke. Although it remains uncertain if consumer-led AF screening reduces stroke, it could increase early diagnosis of AF and facilitate an integrated approach, including appropriate anticoagulation, rate or rhythm management, and risk factor modification to reduce complications. Companies marketing AF screening devices should report the accuracy and performance of their products in high- and low-risk populations and avoid claims about clinical outcomes unless improvement is demonstrated in randomized clinical trials. Generally, the diagnostic yield of AF screening increases with the number, duration, and temporal dispersion of screening sessions, but the prognostic importance may be less than for AF detected by single-time point screening, which is largely permanent, persistent, or high-burden paroxysmal AF. Consumer-initiated ECG recordings suggesting possible AF always require confirmation by a health care professional experienced in ECG reading, whereas suspicion of AF on the basis of photoplethysmography must be confirmed with an ECG. Consumer-led AF screening is unlikely to be cost-effective for stroke prevention in the predominantly young, early adopters of this technology. Studies in older people at higher stroke risk are required to demonstrate both effectiveness and cost-effectiveness. The direct interaction between companies and consumers creates new regulatory gaps in relation to data privacy and the registration of consumer apps and devices. Although several barriers for optimal use of consumer-led screening exist, results of large, ongoing trials, powered to detect clinical outcomes, are required before health care professionals should support widespread adoption of consumer-led AF screening.

Education curriculum assessment for teaching electrocardiography: Rationale and design for the prospective, international, randomized controlled EDUCATE trial.

BACKGROUND: Electrocardiogram (ECG) interpretation training is a fundamental component of medical education across disciplines. However, the skill of interpreting ECGs is not universal among medical graduates, and numerous barriers and challenges exist in medical training and clinical practice. An evidence-based and widely accessible learning solution is needed. DESIGN: The EDUcation Curriculum Assessment for Teaching Electrocardiography (EDUCATE) Trial is a prospective, international, investigator-initiated, open-label, randomized controlled trial designed to determine the efficacy of self-directed and active-learning approaches of a web-based educational platform for improving ECG interpretation proficiency. Target enrollment is 1000 medical professionals from a variety of medical disciplines and training levels. Participants will complete a pre-intervention baseline survey and an ECG interpretation proficiency test. After completion, participants will be randomized into one of four groups in a 1:1:1:1 fashion: (i) an online, question-based learning resource, (ii) an online, lecture-based learning resource, (iii) an online, hybrid question- and lecture-based learning resource, or (iv) a control group with no ECG learning resources. The primary endpoint will be the change in overall ECG interpretation performance according to pre- and post-intervention tests, and it will be measured within and compared between medical professional groups. Secondary endpoints will include changes in ECG interpretation time, self-reported confidence, and interpretation accuracy for specific ECG findings. CONCLUSIONS: The EDUCATE Trial is a pioneering initiative aiming to establish a practical, widely available, evidence-based solution to enhance ECG interpretation proficiency among medical professionals. Through its innovative study design, it tackles the currently unaddressed challenges of ECG interpretation education in the modern era. The trial seeks to pinpoint performance gaps across medical professions, compare the effectiveness of different web-based ECG content delivery methods, and create initial evidence for competency-based standards. If successful, the EDUCATE Trial will represent a significant stride towards data-driven solutions for improving ECG interpretation skills in the medical community.

Demographic, multi-morbidity and genetic impact on myocardial involvement and its recovery from COVID-19: protocol design of COVID-HEART-a UK, multicentre, observational study.

BACKGROUND: Although coronavirus disease 2019 (COVID-19) is primarily a respiratory illness, myocardial injury is increasingly reported and associated with adverse outcomes. However, the pathophysiology, extent of myocardial injury and clinical significance remains unclear. METHODS: COVID-HEART is a UK, multicentre, prospective, observational, longitudinal cohort study of patients with confirmed COVID-19 and elevated troponin (sex-specific > 99th centile). Baseline assessment will be whilst recovering in-hospital or recently discharged, and include cardiovascular magnetic resonance (CMR) imaging, quality of life (QoL) assessments, electrocardiogram (ECG), serum biomarkers and genetics. Assessment at 6-months includes repeat CMR, QoL assessments and 6-min walk test (6MWT). The CMR protocol includes cine imaging, T1/T2 mapping, aortic distensibility, late gadolinium enhancement (LGE), and adenosine stress myocardial perfusion imaging in selected patients. The main objectives of the study are to: (1) characterise the extent and nature of myocardial involvement in COVID-19 patients with an elevated troponin, (2) assess how cardiac involvement and clinical outcome associate with recognised risk factors for mortality (age, sex, ethnicity and comorbidities) and genetic factors, (3) evaluate if differences in myocardial recovery at 6 months are dependent on demographics, genetics and comorbidities, (4) understand the impact of recovery status at 6 months on patient-reported QoL and functional capacity. DISCUSSION: COVID-HEART will provide detailed characterisation of cardiac involvement, and its repair and recovery in relation to comorbidity, genetics, patient-reported QoL measures and functional capacity. CLINICAL TRIAL REGISTRATION: ISRCTN 58667920. Registered 04 August 2020.

Rationale and design of the Medical Research Council's Precision Medicine with Zibotentan in Microvascular Angina (PRIZE) trial.

Microvascular angina is caused by cardiac small vessel disease, and dysregulation of the endothelin system is implicated. The minor G allele of the non-coding single nucleotide polymorphism (SNP) rs9349379 enhances expression of the endothelin 1 gene in human vascular cells, increasing circulating concentrations of ET-1. The prevalence of this allele is higher in patients with ischemic heart disease. Zibotentan is a potent, selective inhibitor of the ETA receptor. We have identified zibotentan as a potential disease-modifying therapy for patients with microvascular angina. METHODS: We will assess the efficacy and safety of adjunctive treatment with oral zibotentan (10 mg daily) in patients with microvascular angina and assess whether rs9349379 (minor G allele; population prevalence ~36%) acts as a theragnostic biomarker of the response to treatment with zibotentan. The PRIZE trial is a prospective, randomized, double-blind, placebo-controlled, sequential cross-over trial. The study population will be enriched to ensure a G-allele frequency of 50% for the rs9349379 SNP. The participants will receive a single-blind placebo run-in followed by treatment with either 10 mg of zibotentan daily for 12 weeks then placebo for 12 weeks, or vice versa, in random order. The primary outcome is treadmill exercise duration using the Bruce protocol. The primary analysis will assess the within-subject difference in exercise duration following treatment with zibotentan versus placebo. CONCLUSION: PRIZE invokes precision medicine in microvascular angina. Should our hypotheses be confirmed, this developmental trial will inform the rationale and design for undertaking a larger multicenter trial.

A counterpoint paper: Comments on the electrocardiographic part of the 2018 Fourth Universal Definition of Myocardial Infarction endorsed by the International Society of Electrocardiology and the International Society for Holter and Noninvasive Electrocardiology.

The Fourth Universal Definition of Myocardial Infarction (FUDMI) focuses on the distinction between nonischemic myocardial injury and myocardial infarction (MI), along with the role of cardiovascular magnetic resonance, in order to define the etiology of myocardial injury. As a consequence, there is less emphasis on updating the parts of the definition concerning the electrocardiographic (ECG) changes related to MI. Evidence of myocardial ischemia is a prerequisite for the diagnosis of MI, and the ECG is the main available tool for (a) detecting acute ischemia, (b) triage, and (c) risk stratification upon presentation. This review focuses on multiple aspects of ECG interpretation that we firmly believe should be considered for incorporation in any future update to the Universal Definition of MI.

An initial exploration of subtraction electrocardiography to detect myocardial ischemia in the prehospital setting.

BACKGROUND: In the prehospital triage of patients presenting with symptoms suggestive of acute myocardial ischemia, reliable myocardial ischemia detection in the electrocardiogram (ECG) is pivotal. Due to large interindividual variability and overlap between ischemic and nonischemic ECG-patterns, incorporation of a previous elective (reference) ECG may improve accuracy. The aim of the current study was to explore the potential value of serial ECG analysis using subtraction electrocardiography. METHODS: SUBTRACT is a multicenter retrospective observational study, including patients who were prehospitally evaluated for acute myocardial ischemia. For each patient, an elective previously recorded reference ECG was subtracted from the ambulance ECG. Patients were classified as myocardial ischemia cases or controls, based on the in-hospital diagnosis. The diagnostic performance of subtraction electrocardiography was tested using logistic regression of 28 variables describing the differences between the reference and ambulance ECGs. The Uni-G ECG Analysis Program was used for state-of-the-art single-ECG interpretation of the ambulance ECG. RESULTS: In 1,229 patients, the mean area-under-the-curve of subtraction electrocardiography was 0.80 (95%CI: 0.77-0.82). The performance of our new method was comparable to single-ECG analysis using the Uni-G algorithm: sensitivities were 66% versus 67% (p-value > .05), respectively; specificities were 80% versus 81% (p-value > .05), respectively. CONCLUSIONS: In our initial exploration, the diagnostic performance of subtraction electrocardiography for the detection of acute myocardial ischemia proved equal to that of state-of-the-art automated single-ECG analysis by the Uni-G algorithm. Possibly, refinement of both algorithms, or even integration of the two, could surpass current electrocardiographic myocardial ischemia detection.

A counterpoint paper: Comments on the electrocardiographic part of the 2018 Fourth Universal Definition of Myocardial Infarction.

The Fourth Universal Definition of Myocardial Infarction (FUDMI) [published simultaneously in 2018 in numerous journals including Circulation, Journal of the American College of Cardiology and European Heart Journal] focuses mainly on the distinction between non-ischemic myocardial injury and myocardial infarction (MI), along with the role of cardiovascular magnetic resonance, in order to define the etiology of myocardial injury. As a consequence, there is less emphasis on updating the parts of the definition concerning the electrocardiographic (ECG) changes related to MI. Evidence of myocardial ischemia is a prerequisite for the diagnosis of MI and the ECG is the main available tool for i) detecting acute ischemia, ii) triage and iii) risk stratification upon presentation. This review focuses on multiple aspects of ECG interpretation that we firmly believe should be considered for incorporation in any future update to the Universal Definition of MI. Our counterpoint view is that: a) the use of the ECG following coronary artery bypass surgery should be better explored and defined; b) the emphasis in the FUDMI on convex versus concave ST-elevation, which is questionable, should be balanced by the fact that many patients with true ST-elevation MI (STEMI) present with a concave form of ST elevation; c) reciprocal ST-depression in STEMI caused by right coronary artery or left circumflex artery occlusion, should be set against the fact that not all anterior STEMIs present with reciprocal ST-depression which can also be seen in cardiomyopathy and left ventricular hypertrophy; d) the "posterior" leads V7-V9 should be placed on a horizontal line from V4, rather than follow the 5th intercostal space; e) ST-depression in V1-V3 is not a manifestation of ischemia of the basal inferior segment, placed horizontally; f) Interpreting ST-T changes in patients with conduction abnormalities and pacemakers should be further defined.

Distinctive ECG patterns in healthy black adults.

Six ECG patterns are found more frequently in healthy black adults than in whites. These patterns are presumably benign, but also may resemble those of malignant disease. 1) Healthy black adults show higher QRS voltage, and more often meet ECG criteria for left ventricular hypertrophy (LVH). Associated repolarization abnormalities can produce ST segment elevation (STE) that resembles ST elevation MI (STEMI). 2) The pattern of benign anterior STE, seen often in males, is more common in black subjects. Similar to LVH, this pattern may falsely suggest STEMI. 3) Both early repolarization (ER) and benign inferolateral STE are more common in black patients. Although they may convey a higher risk of fatal arrhythmias or cardiac death in white populations, it does not appear that black subjects with these patterns show a similar risk. 4) The persistent juvenile T wave inversion pattern shows asymmetric T wave inversion (TWI) in V1-V4, without ST segment deviations. It is most common in black females, and is considered benign. However, this pattern can also resemble the anterior TWI of arrhythmogenic right ventricular cardiomyopathy (ARVC). 5) A pattern of anterior TWI with associated J point elevation is a common finding in the black population, especially athletes. It could suggest hypertrophic cardiomyopathy, but can be presumed to be a benign finding in black athletes, when TWI is limited to V1-V4 and preceded by J point elevation. 6) TWI in the lateral precordial leads, usually associated with end-QRS slurring or notches is seen much more often in apparently healthy black subjects than white subjects. Unlike the anterior TWI pattern, however, it cannot be presumed benign. In conclusion, awareness of these ECG patterns may help to avoid unnecessary diagnostic or therapeutic interventions, but also encourage appropriate investigations.

Tele-electrocardiography and bigdata: The CODE (Clinical Outcomes in Digital Electrocardiography) study.

Digital electrocardiographs are now widely available and a large number of digital electrocardiograms (ECGs) have been recorded and stored. The present study describes the development and clinical applications of a large database of such digital ECGs, namely the CODE (Clinical Outcomes in Digital Electrocardiology) study. ECGs obtained by the Telehealth Network of Minas Gerais, Brazil, from 2010 to 17, were organized in a structured database. A hierarchical free-text machine learning algorithm recognized specific ECG diagnoses from cardiologist reports. The Glasgow ECG Analysis Program provided Minnesota Codes and automatic diagnostic statements. The presence of a specific ECG abnormality was considered when both automatic and medical diagnosis were concordant; cases of discordance were decided using heuristisc rules and manual review. The ECG database was linked to the national mortality information system using probabilistic linkage methods. From 2,470,424 ECGs, 1,773,689 patients were identified. After excluding the ECGs with technical problems and patients <16 years-old, 1,558,415 patients were studied. High performance measures were obtained using an end-to-end deep neural network trained to detect 6 types of ECG abnormalities, with F1 scores >80% and specificity >99% in an independent test dataset. We also evaluated the risk of mortality associated with the presence of atrial fibrillation (AF), which showed that AF was a strong predictor of cardiovascular mortality and mortality for all causes, with increased risk in women. In conclusion, a large database that comprises all ECGs performed by a large telehealth network can be useful for further developments in the field of digital electrocardiography, clinical cardiology and cardiovascular epidemiology.

Effect of Low-Dose Intracoronary Alteplase During Primary Percutaneous Coronary Intervention on Microvascular Obstruction in Patients With Acute Myocardial Infarction: A Randomized Clinical Trial.

Importance: Microvascular obstruction commonly affects patients with acute ST-segment elevation myocardial infarction (STEMI) and is associated with adverse outcomes. Objective: To determine whether a therapeutic strategy involving low-dose intracoronary fibrinolytic therapy with alteplase infused early after coronary reperfusion will reduce microvascular obstruction. Design, Setting, and Participants: Between March 17, 2016, and December 21, 2017, 440 patients presenting at 11 hospitals in the United Kingdom within 6 hours of STEMI due to a proximal-mid-vessel occlusion of a major coronary artery were randomized in a 1:1:1 dose-ranging trial design. Patient follow-up to 3 months was completed on April 12, 2018. Interventions: Participants were randomly assigned to treatment with placebo (n = 151), alteplase 10 mg (n = 144), or alteplase 20 mg (n = 145) by manual infusion over 5 to 10 minutes. The intervention was scheduled to occur early during the primary PCI procedure, after reperfusion of the infarct-related coronary artery and before stent implant. Main Outcomes and Measures: The primary outcome was the amount of microvascular obstruction (% left ventricular mass) demonstrated by contrast-enhanced cardiac magnetic resonance imaging (MRI) conducted from days 2 through 7 after enrollment. The primary comparison was the alteplase 20-mg group vs the placebo group; if not significant, the alteplase 10-mg group vs the placebo group was considered a secondary analysis. Results: Recruitment stopped on December 21, 2017, because conditional power for the primary outcome based on a prespecified analysis of the first 267 randomized participants was less than 30% in both treatment groups (futility criterion). Among the 440 patients randomized (mean age, 60.5 years; 15% women), the primary end point was achieved in 396 patients (90%), 17 (3.9%) withdrew, and all others were followed up to 3 months. In the primary analysis, the mean microvascular obstruction did not differ between the 20-mg alteplase and placebo groups (3.5% vs 2.3%; estimated difference, 1.16%; 95% CI, -0.08% to 2.41%; P = .32) nor in the analysis of 10-mg alteplase vs placebo groups (2.6% vs 2.3%; estimated difference, 0.29%; 95% CI, -0.76% to 1.35%; P = .74). Major adverse cardiac events (cardiac death, nonfatal MI, unplanned hospitalization for heart failure) occurred in 15 patients (10.1%) in the placebo group, 18 (12.9%) in the 10-mg alteplase group, and 12 (8.2%) in the 20-mg alteplase group. Conclusions and Relevance: Among patients with acute STEMI presenting within 6 hours of symptoms, adjunctive low-dose intracoronary alteplase given during the primary percutaneous intervention did not reduce microvascular obstruction. The study findings do not support this treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT02257294.

Genetic Risk Prediction of Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) has a substantial genetic basis. Identification of individuals at greatest AF risk could minimize the incidence of cardioembolic stroke. METHODS: To determine whether genetic data can stratify risk for development of AF, we examined associations between AF genetic risk scores and incident AF in 5 prospective studies comprising 18 919 individuals of European ancestry. We examined associations between AF genetic risk scores and ischemic stroke in a separate study of 509 ischemic stroke cases (202 cardioembolic [40%]) and 3028 referents. Scores were based on 11 to 719 common variants (≥5%) associated with AF at P values ranging from <1×10-3 to <1×10-8 in a prior independent genetic association study. RESULTS: Incident AF occurred in 1032 individuals (5.5%). AF genetic risk scores were associated with new-onset AF after adjustment for clinical risk factors. The pooled hazard ratio for incident AF for the highest versus lowest quartile of genetic risk scores ranged from 1.28 (719 variants; 95% confidence interval, 1.13-1.46; P=1.5×10-4) to 1.67 (25 variants; 95% confidence interval, 1.47-1.90; P=9.3×10-15). Discrimination of combined clinical and genetic risk scores varied across studies and scores (maximum C statistic, 0.629-0.811; maximum ΔC statistic from clinical score alone, 0.009-0.017). AF genetic risk was associated with stroke in age- and sex-adjusted models. For example, individuals in the highest versus lowest quartile of a 127-variant score had a 2.49-fold increased odds of cardioembolic stroke (95% confidence interval, 1.39-4.58; P=2.7×10-3). The effect persisted after the exclusion of individuals (n=70) with known AF (odds ratio, 2.25; 95% confidence interval, 1.20-4.40; P=0.01). CONCLUSIONS: Comprehensive AF genetic risk scores were associated with incident AF beyond associations for clinical AF risk factors but offered small improvements in discrimination. AF genetic risk was also associated with cardioembolic stroke in age- and sex-adjusted analyses. Efforts are warranted to determine whether AF genetic risk may improve identification of subclinical AF or help distinguish between stroke mechanisms.

The Influence of Age and Sex on the Electrocardiogram.

The electrocardiogram (ECG) remains the most commonly used test in medical practice and as such requires to be interpreted with due care and attention to detail. The ECG changes rapidly from birth through childhood with age differences clearly related to increasing QRS voltages and a widening QRS complex. The only sex difference at this age is a slightly longer QRS duration in boys than girls.In adulthood, sex differences in QRS voltage are maximum in the under 40 age group and tend to minimise with advancing age. QRS duration is longer in males than in females, but little difference is made of this in diagnostic criteria. In a similar vein, ST amplitudes are higher in young males compared to young females with the difference diminishing as age increases. Corrected QT interval is longer in females than males.In summary, age and gender differences in the ECG are important and have been incorporated into a variety of criteria for ECG interpretation. Physicians should be aware of the main sex differences in the ECG.

Sex- and Age-Related Reference Values in Cardiology, with Annotations and Guidelines for Interpretation.

The definition of "abnormal" in clinical sciences is often based on so-called reference values which point to a range that experts by some sort of consensus consider as normal when looking at biological variables. Such a level is commonly calculated by taking (twice) the standard deviation from the mean, or considering certain percentiles. The suspicion or even confirmation of a disease is then established by demonstrating that the value measured exceeds the upper or lower reference value. As is often the case, the measurement accuracy may depend on the conditions and specific method employed to collect and analyze data. This implies that, for example, data assessed by 2D echocardiography possibly differ from those obtained by MRI and therefore require modality-specific reference values. In this review we summarize reference values for the electrocardiogram, cardiac compartmental volumes, and arterial vessel size in males and females for various age groups. These values may further depend on other variables such as body size, physical training status, and ethnicity. Additional variables relevant for cardiology such as those referring to the microcirculation and biomarkers are only mentioned with reference to the pertinent literature. In general, the sex- and age-specific differences observed are often remarkable and warrant consideration in clinical practice and basic biomedical sciences.

Annotation of loci from genome-wide association studies using tissue-specific quantitative interaction proteomics.

Genome-wide association studies (GWAS) have identified thousands of loci associated with complex traits, but it is challenging to pinpoint causal genes in these loci and to exploit subtle association signals. We used tissue-specific quantitative interaction proteomics to map a network of five genes involved in the Mendelian disorder long QT syndrome (LQTS). We integrated the LQTS network with GWAS loci from the corresponding common complex trait, QT-interval variation, to identify candidate genes that were subsequently confirmed in Xenopus laevis oocytes and zebrafish. We used the LQTS protein network to filter weak GWAS signals by identifying single-nucleotide polymorphisms (SNPs) in proximity to genes in the network supported by strong proteomic evidence. Three SNPs passing this filter reached genome-wide significance after replication genotyping. Overall, we present a general strategy to propose candidates in GWAS loci for functional studies and to systematically filter subtle association signals using tissue-specific quantitative interaction proteomics.

Liver enzymes are not directly involved in atrial fibrillation: a prospective cohort study.

BACKGROUND: Epidemiological evidence proposes the direct involvement of the liver enzymes in atrial fibrillation. These relationships are controversial and mechanistically unclear. As part of the British Regional Heart Study, we investigated whether change in liver enzymes over time associates with atrial fibrillation in men initially free of this heart condition. MATERIALS AND METHODS: We prospectively investigated change (delta) in liver enzymes and new-onset atrial fibrillation in a representative sample of 1428 men aged 60-79 years. RESULTS: Mean follow-up was 12·3 years, after which 108 new atrial fibrillation cases were identified. The liver enzymes did not differ at baseline or follow-up, except for gamma-glutamyl transferase which was higher at follow-up in men who developed atrial fibrillation compared to those who did not (P < 0·0001). Change in GGT was greater in men who developed AF than those who did not (+6·12 vs. -2·60 U/L, P = 0·036). N-terminal pro-brain natriuretic peptide (baseline and follow-up, P < 0·0001) and total bilirubin (follow-up only, P < 0·0001) were also higher in men who developed atrial fibrillation while serum haemoglobin was similar at baseline and follow-up (P ≥ 0·74). Atrial fibrillation was associated with change in gamma-glutamyl transferase (OR, 1·18; 95% CI, 1·01-1·37) after multiple adjustments and exclusions. However, after adjusting for baseline (P = 0·088) or change (P = 0·40) in N-terminal pro-brain natriuretic peptide, the association between atrial fibrillation and change in gamma-glutamyl transferase was lost. CONCLUSION: The direct relationship between atrial fibrillation and liver enzymes is absent and depends, at least in part, on the progression of heart failure as captured by N-terminal pro-brain natriuretic peptide.

Normal limits of the electrocardiogram derived from a large database of Brazilian primary care patients.

BACKGROUND: Knowledge of the normal limits of the electrocardiogram (ECG) is mandatory for establishing which patients have abnormal ECGs. No studies have assessed the reference standards for a Latin American population. Our aim was to establish the normal ranges of the ECG for pediatric and adult Brazilian primary care patients. METHODS: This retrospective observational study assessed all the consecutive 12-lead digital electrocardiograms of primary care patients at least 1 year old in Minas Gerais state, Brazil, recorded between 2010 and 2015. ECGs were excluded if there were technical problems, selected abnormalities were present or patients with selected self-declared comorbidities or on drug therapy. Only the first ECG from patients with multiple ECGs was accepted. The University of Glasgow ECG analysis program was used to automatically interpret the ECGs. For each variable, the 1st, 2nd, 50th, 98th and 99th percentiles were determined and results were compared to selected studies. RESULTS: A total of 1,493,905 ECGs were recorded. 1,007,891 were excluded and 486.014 were analyzed. This large study provided normal values for heart rate, P, QRS and T frontal axis, P and QRS overall duration, PR and QT overall intervals and QTc corrected by Hodges, Bazett, Fridericia and Framingham formulae. Overall, the results were similar to those from other studies performed in different populations but there were differences in extreme ages and specific measurements. CONCLUSIONS: This study has provided reference values for Latinos of both sexes older than 1 year. Our results are comparable to studies performed in different populations.

Causes of Prehospital Misinterpretations of ST Elevation Myocardial Infarction.

OBJECTIVES: To determine the causes of software misinterpretation of ST elevation myocardial infarction (STEMI) compared to clinically identified STEMI to identify opportunities to improve prehospital STEMI identification. METHODS: We compared ECGs acquired from July 2011 through June 2012 using the LIFEPAK 15 on adult patients transported by the Los Angeles Fire Department. Cases included patients ≥18 years who received a prehospital ECG. Software interpretation of the ECG (STEMI or not) was compared with data in the regional EMS registry to classify the interpretation as true positive (TP), true negative (TN), false positive (FP), or false negative (FN). For cases where classification was not possible using registry data, 3 blinded cardiologists interpreted the ECG. Each discordance was subsequently reviewed to determine the likely cause of misclassification. The cardiologists independently reviewed a sample of these discordant ECGs and the causes of misclassification were updated in an iterative fashion. RESULTS: Of 44,611 cases, 50% were male (median age 65; inter-quartile range 52-80). Cases were classified as 482 (1.1%) TP, 711 (1.6%) FP, 43371 (97.2%) TN, and 47 (0.11%) FN. Of the 711 classified as FP, 126 (18%) were considered appropriate for, though did not undergo, emergent coronary angiography, because the ECG showed definite (52 cases) or borderline (65 cases) ischemic ST elevation, a STEMI equivalent (5 cases) or ST-elevation due to vasospasm (4 cases). The sensitivity was 92.8% [95% CI 90.6, 94.7%] and the specificity 98.7% [95% CI 98.6, 98.8%]. The leading causes of FP were ECG artifact (20%), early repolarization (16%), probable pericarditis/myocarditis (13%), indeterminate (12%), left ventricular hypertrophy (8%), and right bundle branch block (5%). There were 18 additional reasons for FP interpretation (<4% each). The leading causes of FN were borderline ST-segment elevations less than the algorithm threshold (40%) and tall T waves reducing the ST/T ratio below threshold (15%). There were 11 additional reasons for FN interpretation occurring ≤3 times each. CONCLUSION: The leading causes of FP automated interpretation of STEMI were ECG artifact and non-ischemic causes of ST-segment elevation. FN were rare and were related to ST-segment elevation or ST/T ratio that did not meet the software algorithm threshold.