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Background: Childhood cancer survivors at risk for heart failure undergo lifelong echocardiographic surveillance. Previous studies reported the limited diagnostic accuracy of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) in detecting left ventricular (LV) dysfunction. However, potential enhanced diagnostic accuracy through the combination of biomarkers and clinical characteristics has been suggested. Objectives: The aim of this study was to develop and internally validate a diagnostic model that combines cardiac biomarkers with clinical characteristics for effectively ruling in or ruling out LV dysfunction in childhood cancer survivors. Methods: A multicenter cross-sectional study included 1,334 survivors (median age 34.2 years) and 278 siblings (median age 36.8 years). Logistic regression models were developed and validated through bootstrapping, combining biomarkers with clinical characteristics. Results: Abnormal NT-proBNP levels were observed in 22.1% of survivors compared with 5.4% of siblings, whereas hs-cTnT levels exceeding 10 ng/L were uncommon in both survivors (5.9%) and siblings (5.0%). The diagnostic models demonstrated improvement upon the addition of NT-proBNP and hs-cTnT to clinical characteristics, resulting in an increased C statistic from 0.69 to 0.73 for LV ejection fraction (LVEF) <50% and a more accurate prediction of more severe LV dysfunction, with the C statistic increasing from 0.80 to 0.86 for LVEF <45%. For LVEF <50% (prevalence 10.9%), 16.9% of survivors could be effectively ruled out with high sensitivity (95.4%; 95% CI: 90.4%-99.3%) and negative predictive value (97.5%; 95% CI: 94.6%-99.7%). Similarly, for LVEF <45% (prevalence 3.4%), 53.0% of survivors could be ruled out with moderate to high sensitivity (91.1%; 95% CI: 79.2%-100%) and high negative predictive value (99.4%; 95% CI: 98.7%-100%). Conclusions: The biomarker-based diagnostic model proves effective in ruling out LV dysfunction, offering the potential to minimize unnecessary surveillance echocardiography in childhood cancer survivors. External validation is essential to confirm these findings. (Early Detection of Cardiac Dysfunction in Childhood Cancer Survivors; A DCOG LATER Study; https://onderzoekmetmensen.nl/nl/trial/23641).
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OBJECTIVE: Longitudinal consequences and potential interactions of COVID-19 and elite-level sports and exercise are unclear. Therefore, we determined the long-term detrimental cardiac effects of the interaction between SARS-CoV-2 infection and the highest level of sports and exercise. METHODS: This prospective controlled study included elite athletes from the Evaluation of Lifetime participation in Intensive Top-level sports and Exercise cohort. Athletes infected with SARS-CoV-2were offered structured, additional cardiovascular screenings, including cardiovascular MRI (CMR). We compared ventricular volumes and function, late gadolinium enhancement (LGE) and T1 relaxation times, between infected and non-infected elite athletes, and collected follow-up data on cardiac adverse events, ventricular arrhythmia burden and the cessation of sports careers. RESULTS: We included 259 elite athletes (mean age 26±5 years; 40% women), of whom 123 were infected (9% cardiovascular symptoms) and 136 were controls. We found no differences in function and volumetric CMR parameters. Four infected athletes (3%) demonstrated LGE (one reversible), compared with none of the controls. During the 26.7 (±5.8) months follow-up, all four athletes resumed elite-level sports, without an increase in ventricular arrhythmias or adverse cardiac remodelling. None of the infected athletes reported new cardiac symptoms or events. The majority (n=118; 96%) still participated in elite-level sports; no sports careers were terminated due to SARS-CoV-2. CONCLUSIONS: This prospective study demonstrates the safety of resuming elite-level sports after SARS-CoV-2 infection. The medium-term risks associated with SARS-CoV-2 infection and elite-level sports appear low, as the resumption of elite sports did not lead to detrimental cardiac effects or increases in clinical events, even in the four elite athletes with SARS-CoV-2 associated myocardial involvement.
Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Female , Young Adult , Adult , Male , Prospective Studies , Follow-Up Studies , Contrast Media , COVID-19/epidemiology , Gadolinium , Athletes , Arrhythmias, Cardiac/epidemiology , Arrhythmias, Cardiac/etiologyABSTRACT
The recognition of myocarditis as a rare side effect of SARS-CoV-2 mRNA vaccination has sparked a global debate on vaccine safety, especially in the realm of sports. The main proposed mechanisms in the pathogenesis of COVID-19 mRNA vaccination-associated myocarditis (C-VAM) are based on the activation of the innate- and adaptive immune system against a susceptible immune-genetic background, including the recognition of mRNA as an antigen by the immune system, molecular mimicry between SARS-CoV-2 spike glycoprotein and cardiac tissue antigens and inflammatory sex-hormone signalling. The relatively younger age of the athlete population hypothetically constellates an increased risk of C-VAM. A subgroup analysis in individuals under 40 years revealed a low incidence of myocarditis following COVID-19 mRNA vaccination when compared to positive SARS-CoV-2 tests. No confirmed cases of athletes experiencing cardiac complications after mRNA vaccination have been reported. Most athletes only reported mild side effects after COVID-19 vaccination. A small but statistically significant decrease in maximal oxygen consumption in recreational athletes occurred after BNT162b2 mRNA booster vaccine administration. The clinical relevance and temporality of which remain to be determined. Many speculative social media reports attribute sudden cardiac arrest/death (SCA/D) in athletes to mRNA vaccination. Large media outlets have thoroughly debunked these claims. There is currently no evidence to support the claim that COVID-19 mRNA vaccination increases the risk of myocardial sequelae or SCA/D in athletes. However, specific vaccine regimen selection and timing may be appropriate to prevent detrimental performance effects.
Subject(s)
COVID-19 Vaccines , COVID-19 , Myocarditis , Humans , Athletes , BNT162 Vaccine , Communication , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Death, Sudden, Cardiac/etiology , Death, Sudden, Cardiac/prevention & control , Disease Progression , Myocarditis/chemically induced , RNA, Messenger , SARS-CoV-2 , Vaccination/adverse effectsABSTRACT
Circular RNAs (circRNAs) are a class of non-coding RNA molecules that are gaining increasing attention for their roles in various pathophysiological processes. The RNA-binding protein quaking (QKI) has been identified as a regulator of circRNA formation. In this study, we investigate the role of QKI in the formation of circRNAs in the heart by performing RNA-sequencing on Qki-knockout mice. Loss of QKI resulted in the differential expression of 17% of the circRNAs in adult mouse hearts. Interestingly, the majority of the QKI-regulated circRNAs (58%) were derived from genes undergoing QKI-dependent splicing, indicating a relationship between back-splicing and linear splicing. We compared these QKI-dependent circRNAs with those regulated by RBM20, another cardiac splicing factor essential for circRNA formation. We found that QKI and RBM20 regulate the formation of a distinct, but partially overlapping set of circRNAs in the heart. Strikingly, many shared circRNAs were derived from the Ttn gene, and they were regulated in an opposite manner. Our findings indicate that QKI not only regulates alternative splicing in the heart but also the formation of circRNAs.
Subject(s)
Myocytes, Cardiac , RNA, Circular , Mice , Animals , RNA, Circular/genetics , RNA, Circular/metabolism , Myocytes, Cardiac/metabolism , Alternative Splicing/genetics , RNA Splicing , Mice, Knockout , RNA/genetics , RNA/metabolism , RNA-Binding Proteins/metabolismABSTRACT
BACKGROUND: Recent advances in multi-marker platforms offer faster data generation, but the fidelity of these methods compared to the ELISA is not established. We tested the correlation and predictive performance of SOMAscan vs. ELISA methods for NTproBNP and ST2. METHODS: Patients ≥ 18 years with heart failure and ejection fraction < 50% were enrolled. We tested the correlation between SOMA and ELISA for each biomarker and their association with outcomes. RESULTS: There was good correlation of SOMA vs. ELISA for ST2 (ρ = 0.71) and excellent correlation for NTproBNP (ρ = 0.94). The two versions of both markers were not significantly different regarding survival association. The two ST2 assays and NTproBNP assays were similarly associated with all-cause mortality and cardiovascular mortality. These associations remained statistically significant when adjusted for MAGGIC risk score (all p < 0.05). CONCLUSION: SOMAscan quantifications of ST2 and NTproBNP correlate to ELISA versions and carry similar prognosis.
Subject(s)
Heart Failure , Natriuretic Peptide, Brain , Humans , Interleukin-1 Receptor-Like 1 Protein , Prognosis , Heart Failure/diagnosis , Peptide Fragments , BiomarkersABSTRACT
Alternative splicing generates specialized protein isoforms that allow the heart to adapt during development and disease. The recent discovery that mutations in the splicing factor RNA-binding protein 20 (RBM20) cause a severe form of familial dilated cardiomyopathy has sparked a great interest in alternative splicing in the field of cardiology. Since then, identification of splicing factors controlling alternative splicing in the heart has grown at a rapid pace. Despite the intriguing observation that a certain overlap exists between the targets of some splicing factors, an integrated and systematic analysis of their splicing networks is missing. Here, we compared the splicing networks of individual splicing factors by re-analyzing original RNA-sequencing data from eight previously published mouse models, in which a single splicing factor has been genetically deleted (i.e. HNRNPU, MBNL1/2, QKI, RBM20, RBM24, RBPMS, SRSF3, SRSF4). We show that key splicing events in Camk2d, Ryr2, Tpm1, Tpm2 and Pdlim5 require the combined action of the majority of these splicing factors. Additionally, we identified common targets and pathways among splicing factors, with the largest overlap between the splicing networks of MBNL, QKI and RBM24. We also re-analyzed a large-scale RNA-sequencing study on hearts of 128 heart failure patients. Here, we observed that MBNL1, QKI and RBM24 expression varied greatly. This variation in expression correlated with differential splicing of their downstream targets as found in mice, suggesting that aberrant splicing by MBNL1, QKI and RBM24 might contribute to the disease mechanism in heart failure.
Subject(s)
Heart Failure , Heart , Mice , Animals , RNA Splicing Factors/genetics , RNA Splicing Factors/metabolism , Alternative Splicing/genetics , Heart Failure/genetics , Heart Failure/metabolism , RNA/metabolism , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolismABSTRACT
Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. We here report results from the largest HCM genome-wide association study (GWAS) and multi-trait analysis (MTAG) including 5,900 HCM cases, 68,359 controls, and 36,083 UK Biobank (UKB) participants with cardiac magnetic resonance (CMR) imaging. We identified a total of 70 loci (50 novel) associated with HCM, and 62 loci (32 novel) associated with relevant left ventricular (LV) structural or functional traits. Amongst the common variant HCM loci, we identify a novel HCM disease gene, SVIL, which encodes the actin-binding protein supervillin, showing that rare truncating SVIL variants cause HCM. Mendelian randomization analyses support a causal role of increased LV contractility in both obstructive and non-obstructive forms of HCM, suggesting common disease mechanisms and anticipating shared response to therapy. Taken together, the findings significantly increase our understanding of the genetic basis and molecular mechanisms of HCM, with potential implications for disease management.
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Introduction: The cardiovascular benefits of physical exercise are well-known. However, vigorous exercise has also been associated with adverse cardiac effects. To improve our understanding of cardiovascular adaptation to exercise versus maladaptation and pathology, the limits of adaptation should be firmly established using state-of-the-art diagnostic modalities. We therefore initiated the Evaluation of Lifetime participation in Intensive Top-level sports and Exercise (ELITE) cohort to investigate the longitudinal (beneficial and pathological) cardiovascular effects of intensive elite sports and exercise. Methods and analysis: ELITE is a prospective, multicentre, longitudinal cohort study. Elite athletes, from the age of sixteen, are recruited in The Netherlands. The primary objective is to determine the association between elite sports and exercise-induced cardiac remodelling, cardiac pathology, and health benefits over time. Secondary objectives include determining and identifying genetic profiles of elite athletes, and how these are associated with cardiac indices. ELITE will collect data from consultations, electrocardiography, echocardiography and cardiac magnetic resonance imaging, and training- and injury data. ELITE will also collect blood for biobanking and cardiogenetics. Follow-up will take place at intervals of two to five years, and after the elite athletes' professional careers have ended. In addition, a subcohort of ELITE has been established to investigate cardiac sequelae following infections associated with myocardial involvement, including SARS-CoV-2. ELITE is a prospective observational study; therefore, analyses will be primarily explorative. Ethics and dissemination: This study has been approved by the Medical Ethics Review Board of the Amsterdam University Medical Centers (NL71682.018.19). The results of the study will be disseminated by publication in peer-reviewed journals (Netherlands Trial Register number: NL9328).
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BACKGROUND: Cardiac involvement in idiopathic inflammatory myopathy (IIM or "myositis") is associated with an approximate 4% mortality, but standardised screening strategies are lacking. OBJECTIVE: We explored a multimodality screening on potentially reversible cardiac involvement -i.e. active (peri)myocarditis -in newly diagnosed IIM. METHODS: We included adult IIM patients from 2017 to 2020. At time of diagnosis, patients underwent cardiac evaluation including laboratory biomarkers, electrocardiography, echocardiography, and cardiac magnetic resonance imaging (CMR). Based on 2019 consensus criteria for myocarditis, an adjudication committee made diagnoses of definite, probable, possible or no (peri)myocarditis. We explored diagnostic values of sequentially added diagnostic modalities by Constructing Classification and Regression Tree (CART) analysis in patients with definite/probable versus no (peri)myocarditis. RESULTS: We included 34 IIM patients, in whom diagnoses of definite (six, 18%), probable (two, 6%), possible (11, 32%), or no (peri)myocarditis (15, 44%) were adjudicated. CART-analysis showed high-sensitivity cardiac troponin T (cut-off valueâ<â2.3 times the upper limit of normal (xULN)) ruled out (peri)myocarditis with a sensitivity of 88%, while high-sensitivity troponin I (cut-off valueâ>â2.9 xULN for females andâ>â1.8 xULN for males) ruled in (peri)myocarditis with a specificity of 100%. Applying high-sensitivity cardiac troponins with these cut-off values in a diagnostic algorithm without and with a CMR to the total population of 34 patients demonstrated a diagnostic accuracy for a clear diagnosis of probable/definite or no (peri)myocarditis of 59% and 68%, respectively. CONCLUSIONS: A diagnostic algorithm for detection of (peri)myocarditis in adult IIM may consist of sequential testing with high-sensitivity cardiac troponins and CMR.
Subject(s)
Myocarditis , Myositis , Adult , Male , Female , Humans , Myocarditis/complications , Cross-Sectional Studies , Myositis/diagnosis , Heart , Troponin IABSTRACT
AIMS: In the heart, splicing factors orchestrate the functional properties of cardiomyocytes by regulating the alternative splicing of multiple genes. Work in embryonic stem cells has shown that the splicing factor Quaking (QKI) regulates alternative splicing during cardiomyocyte differentiation. However, the relevance and function of QKI in adult cardiomyocytes remains unknown. In this study, we aim to identify the in vivo function of QKI in the adult mouse heart. METHODS AND RESULTS: We generated mice with conditional deletion of QKI in cardiomyocytes by the Cre-Lox system. Mice with cardiomyocyte-specific deletion of QKI died during the foetal period (E14.5), without obvious anatomical abnormalities of the heart. Adult mice with tamoxifen-inducible QKI deletion rapidly developed heart failure associated with severe disruption of sarcomeres, already 7 days after knocking out QKI. RNA sequencing revealed that QKI regulates the alternative splicing of more than 1000 genes, including sarcomere and cytoskeletal components, calcium-handling genes, and (post-)transcriptional regulators. Many of these splicing changes corresponded to the loss of muscle-specific isoforms in the heart. Forced overexpression of QKI in cultured neonatal rat ventricular myocytes directed these splicing events in the opposite direction and enhanced contractility of cardiomyocytes. CONCLUSION: Altogether, our findings show that QKI is an important regulator of the muscle-specific alternative splicing program that builds the contractile apparatus of cardiomyocytes.
Subject(s)
Alternative Splicing , Myocytes, Cardiac , Mice , Rats , Animals , Myocytes, Cardiac/metabolism , Protein Isoforms/genetics , Protein Isoforms/metabolism , Cell Communication , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolismABSTRACT
BACKGROUND: Studies on serially measured GDF-15 (growth differentiation factor 15) in acute heart failure (HF) are limited. Moreover, several pathophysiological pathways contribute to HF. Therefore, we aimed to explore the (additional) prognostic value of serially measured GDF-15 using a multi-marker approach to more accurately predict HF risk. METHODS: TRIUMPH (Translational Initiative on Unique and Novel Strategies for Management of Patients With Heart Failure) is a prospective cohort of 496 patients with acute HF who were enrolled in 14 hospitals in the Netherlands between 2009 and 2014. Blood sampling was scheduled at 7 moments during 1-year follow-up. GDF-15, NT-proBNP (N-terminal pro-B-type natriuretic peptide), ST2 (suppression of tumorigenicity 2), galectin-3, troponin I, and creatinine were measured in a central laboratory. We associated repeated measurements of these biomarkers with the composite primary end point of all-cause mortality and HF rehospitalization, using multivariable joint modeling. RESULTS: Median age was 74 years, and 37% were women. Median baseline GDF-15 was 4632 pg/mL. The primary end point was reached in 188 (40%) patients. The average estimated GDF-15 level increased weeks before the primary end point was reached. The hazard ratio per 1 SD difference in log-GDF-15 was 2.14 (95% CI, 1.78-2.57) unadjusted, 1.96 (1.49-2.53) after adjustment for clinical confounders and 1.44 (1.05-1.91) when jointly modeled with all biomarkers. The adjusted HRs for NT-proBNP were 2.38 (1.78-3.33) and 1.52 (1.15-2.08), respectively. The multimarker model combining GDF-15, NT-proBNP, and troponin I provided a favorable risk discrimination (area under the curve=0.785). CONCLUSIONS: Sequentially measured GDF-15 independently and dynamically predicts risk of adverse outcomes during 1-year follow-up after index admission for acute HF. NT-proBNP remains a robust predictor among potential candidates. Multiple biomarkers should be considered for stratification in clinical practice. REGISTRATION: URL: https://www.trialregister.nl/trial/1783; Unique Identifier: NTR1893. (The trial can be found temporarily at https://trialsearch.who.int/Trial2.aspx?TrialID=NTR1893.).
Subject(s)
Heart Failure , Natriuretic Peptide, Brain , Humans , Female , Aged , Male , Growth Differentiation Factor 15 , Interleukin-1 Receptor-Like 1 Protein , Creatinine , Prospective Studies , Heart Failure/etiology , Troponin I , Prognosis , Biomarkers , Peptide FragmentsABSTRACT
The number of inherited heart disease (IHD) studies using artificial intelligence (AI) has increased rapidly over the last years. In this scoping review, we aimed to present an overview of the current literature available on the applicability of AI within the field of IHD. The literature search resulted in eighteen articles in which an AI model was trained and tested, mostly for diagnostic and predictive purposes. The areas under the receiver operating characteristic curves ranged from 0.78-0.96, but varied between IHD types, used methods and outcome measures. Only three out of eighteen did perform validation on an external dataset and most studies did not use explainable deep learning models. To be able to integrate AI as a tool to aid physicians in their diagnoses and clinical decisions within the IHD field, generalizability has to be better evaluated and explainability of DL models has to be increased.
Subject(s)
Artificial Intelligence , Heart Diseases , Humans , HeartABSTRACT
Objective: To systematically investigate and document the infrastructure, practices, recommendations, and clinical consequences of a structured, organized sports cardiology multidisciplinary team (MDT) for athletes and patients who wish to engage in sports and exercise. Patients and Methods: We established bimonthly sports cardiology MDT meetings, with a permanent panel of experts in sports cardiology, genetics, pediatric cardiology, cardiovascular imaging, electrophysiology, and sports and exercise medicine. Cases were referred nationally or internationally by cardiologists/sports physicians. We retrospectively analyzed all MDT cases (April 10, 2019 through May 13, 2020) and collected clinical follow-up data up to 1 year after the initial review. Results: A total of 115 athletes underwent MDT review; of them, 11% were women, 65% were recreational athletes, and 54% were performing "mixed" type of sports; the mean age was 32±16 years. An MDT review led to a diagnosis revision of "suspected cardiac pathology" to "no cardiac pathology" in 38% of the athletes and increased the number of definitive diagnoses (from 77 to 109; P=.03). We observed fewer "total sports restrictions" (from 6 to 0; P=.04) and more tailored sports advice concerning "no peak load/specific maximum load" (from 10 to 26; P=.02). At the 14±6-month follow-up, 112 (97%) athletes reported no cardiovascular events, 111 (97%) athletes reported no (new) cardiac symptoms, 113 (98%) athletes reported adherence to the MDT sports advice, and no diagnoses were revised. Conclusion: Our experiences with a comprehensive sports cardiology MDT demonstrate that this approach leads to higher percentages of definitive diagnoses and fewer cardiac pathology diagnoses, more tailored sports advice with excellent rates of adherence, and fewer total sports restrictions. Our findings highlight the added value of sports cardiology MDTs for patient and athlete care.
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Background: COVID-19 has been associated with myocardial abnormalities on cardiac magnetic resonance imaging (CMR). We report a case of COVID-19 myocarditis in an elite athlete. Case summary: A male, 21-year-old elite football player had tested positive for SARS-CoV-2 on a polymerase-chain-reaction test and was referred for cardiac evaluation after experiencing palpitations after returning to sports (RTS). Biochemical evaluation demonstrated elevated N-terminal pro b-type natriuretic peptide (NT-proBNP) and high-sensitive Troponin T. Echocardiography demonstrated left ventricular function within normal ranges for athletes but with diminished basal, posterolateral, and septal strain. Cardiac magnetic resonance imaging (CMR) showed increased T1 values and late gadolinium enhancement (LGE) in the basolateral and mid-ventricular posterior segments. Focal COVID-19 myocarditis was diagnosed and the patient remained restricted from sports, in line with the 2020 ESC sports cardiology guidelines. Two months later, his electrocardiogram (ECG) showed inferoposterolateral T-wave inversion (TWI). Serial imaging studies were performed to optimize RTS timing. Cardiac magnetic resonance imaging showed persistently increased T1/T2 values and persistent LGE at 5 and 7 months. At 9 months, 18â F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)-computerized tomography (CT) demonstrated no pathologically increased cardiac FDG-uptake. Subsequent exercise ECG and Holters demonstrated no complex ventricular arrhythmias. The patient made a complete return to elite competitive sports, without any adverse events at 15 months of follow-up. Discussion: Cardiac symptoms in athletes post-COVID-19 should prompt cardiac evaluation. As COVID-19 myocarditis inflammation can persist beyond the 3-6 months of recommended sports restriction, a more personalized approach to RTS timing can be warranted. In cases with myocardial oedema without other signs of inflammation, FDG-PET-CT can be of added value to assess active myocardial inflammation.
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Background Plasma biomarkers may aid in the detection of anthracycline-related cardiomyopathy (ACMP). However, the currently available biomarkers have limited diagnostic value in long-term childhood cancer survivors. This study sought to identify diagnostic plasma biomarkers for ACMP in childhood cancer survivors. Methods and Results We measured 275 plasma proteins in 28 ACMP cases with left ventricular ejection fraction <45%, 29 anthracycline-treated controls with left ventricular ejection fraction ≥53% matched on sex, time after cancer, and anthracycline dose, and 29 patients with genetically determined dilated cardiomyopathy with left ventricular ejection fraction <45%. Multivariable linear regression was used to identify differentially expressed proteins. Elastic net model, including clinical characteristics, was used to assess discrimination of proteins diagnostic for ACMP. NT-proBNP (N-terminal pro-B-type natriuretic peptide) and the inflammatory markers CCL19 (C-C motif chemokine ligands 19) and CCL20, PSPD (pulmonary surfactant protein-D), and PTN (pleiotrophin) were significantly upregulated in ACMP compared with controls. An elastic net model selected 45 proteins, including NT-proBNP, CCL19, CCL20 and PSPD, but not PTN, that discriminated ACMP cases from controls with an area under the receiver operating characteristic curve (AUC) of 0.78. This model was not superior to a model including NT-proBNP and clinical characteristics (AUC=0.75; P=0.766). However, when excluding 8 ACMP cases with heart failure, the full model was superior to that including only NT-proBNP and clinical characteristics (AUC=0.75 versus AUC=0.50; P=0.022). The same 45 proteins also showed good discrimination between dilated cardiomyopathy and controls (AUC=0.89), underscoring their association with cardiomyopathy. Conclusions We identified 3 specific inflammatory proteins as candidate plasma biomarkers for ACMP in long-term childhood cancer survivors and demonstrated protein overlap with dilated cardiomyopathy.
Subject(s)
Cancer Survivors , Cardiomyopathies , Cardiomyopathy, Dilated , Neoplasms , Anthracyclines/adverse effects , Antibiotics, Antineoplastic/adverse effects , Biomarkers , Cardiomyopathies/chemically induced , Cardiomyopathies/diagnosis , Case-Control Studies , Child , Humans , Natriuretic Peptide, Brain , Neoplasms/chemically induced , Neoplasms/drug therapy , Peptide Fragments , Stroke Volume , Ventricular Function, LeftABSTRACT
BACKGROUND: Congenital long QT syndrome (LQTS) is a rare heart disease caused by various underlying mutations. Most general cardiologists do not routinely see patients with congenital LQTS and may not always recognize the accompanying ECG features. In addition, a proportion of disease carriers do not display obvious abnormalities on their ECG. Combined, this can cause underdiagnosing of this potentially life-threatening disease. METHODS: This study presents 1D convolutional neural network models trained to identify genotype positive LQTS patients from electrocardiogram as input. The deep learning (DL) models were trained with a large 10-s 12-lead ECGs dataset provided by Amsterdam UMC and externally validated with a dataset provided by University Hospital Leuven. The Amsterdam dataset included ECGs from 10000 controls, 172 LQTS1, 214 LQTS2, and 72 LQTS3 patients. The Leuven dataset included ECGs from 2200 controls, 32 LQTS1, and 80 LQTS2 patients. The performance of the DL models was compared with conventional QTc measurement and with that of an international expert in congenital LQTS (A.A.M.W). Lastly, an explainable artificial intelligence (AI) technique was used to better understand the prediction models. RESULTS: Overall, the best performing DL models, across 5-fold cross-validation, achieved on average a sensitivity of 84 ± 2%, 90 ± 2% and 87 ± 6%, specificity of 96 ± 2%, 95 ± 1%, and 92 ± 4%, and AUC of 0.90 ± 0.01, 0.92 ± 0.02, and 0.89 ± 0.03, for LQTS 1, 2, and 3 respectively. The DL models were also shown to perform better than conventional QTc measurements in detecting LQTS patients. Furthermore, the performances held up when the DL models were validated on a novel external cohort and outperformed the expert cardiologist in terms of specificity, while in terms of sensitivity, the DL models and the expert cardiologist in LQTS performed the same. Finally, the explainable AI technique identified the onset of the QRS complex as the most informative region to classify LQTS from non-LQTS patients, a feature previously not associated with this disease. CONCLUSIONS: This study suggests that DL models can potentially be used to aid cardiologists in diagnosing LQTS. Furthermore, explainable DL models can be used to possibly identify new features for LQTS on the ECG, thus increasing our understanding of this syndrome.
Subject(s)
Deep Learning , Long QT Syndrome , Artificial Intelligence , Electrocardiography/methods , Humans , Long QT Syndrome/congenital , Long QT Syndrome/diagnosis , Long QT Syndrome/genetics , Neural Networks, ComputerABSTRACT
Long-QT syndrome type 1 (LQT1) is caused by mutations in KCNQ1. Patients heterozygous for such a mutation co-assemble both mutant and wild-type KCNQ1-encoded subunits into tetrameric Kv7.1 potassium channels. Here, we investigated whether allele-specific inhibition of mutant KCNQ1 by targeting a common variant can shift the balance towards increased incorporation of the wild-type allele to alleviate the disease in human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs). We identified the single nucleotide polymorphisms (SNP) rs1057128 (G/A) in KCNQ1, with a heterozygosity of 27% in the European population. Next, we determined allele-specificity of short-hairpin RNAs (shRNAs) targeting either allele of this SNP in hiPSC-CMs that carry an LQT1 mutation. Our shRNAs downregulated 60% of the A allele and 40% of the G allele without affecting the non-targeted allele. Suppression of the mutant KCNQ1 allele by 60% decreased the occurrence of arrhythmic events in hiPSC-CMs measured by a voltage-sensitive reporter, while suppression of the wild-type allele increased the occurrence of arrhythmic events. Furthermore, computer simulations based on another LQT1 mutation revealed that 60% suppression of the mutant KCNQ1 allele shortens the prolonged action potential in an adult cardiomyocyte model. We conclude that allele-specific inhibition of a mutant KCNQ1 allele by targeting a common variant may alleviate the disease. This novel approach avoids the need to design shRNAs to target every single mutation and opens up the exciting possibility of treating multiple LQT1-causing mutations with only two shRNAs.