Frequency Analysis of Atrial Fibrillation From the Surface Electrocardiogram

Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. Neither the natural history of AF nor its response to therapy are sufficiently predictable by clinical and echocardiographic parameters. Atrial fibrillatory frequency (or rate) can reliably be assessed from the surface electrocardiogram (ECG) using digital signal processing (filtering, subtraction of averaged QRST complexes, and power spectral analysis) and shows large inter-individual variability. This measurement correlates well with intraatrial cycle length, a parameter which appears to have primary importance in AF domestication and response to therapy. AF with a low fibrillatory rate is more likely to terminate spontaneously, and responds better to antiarrhythmic drugs or cardioversion while high rate AF is more often persistent and refractory to therapy. In conclusion, frequency analysis of AF seems to be useful for non-invasive assessment of electrical remodeling in AF and may subsequently be helpful for guiding AF therapy

Integration of Attributes from Non-Linear Characterization of Cardiovascular Time-Series for Prediction of Defibrillation Outcomes

Objective The timing of defibrillation is mostly at arbitrary intervals during cardio-pulmonary resuscitation (CPR), rather than during intervals when the out-of-hospital cardiac arrest (OOH-CA) patient is physiologically primed for successful countershock. Interruptions to CPR may negatively impact defibrillation success. Multiple defibrillations can be associated with decreased post-resuscitation myocardial function. We hypothesize that a more complete picture of the cardiovascular system can be gained through non-linear dynamics and integration of multiple physiologic measures from biomedical signals. Materials and Methods Retrospective analysis of 153 anonymized OOH-CA patients who received at least one defibrillation for ventricular fibrillation (VF) was undertaken. A machine learning model, termed Multiple Domain Integrative (MDI) model, was developed to predict defibrillation success. We explore the rationale for non-linear dynamics and statistically validate heuristics involved in feature extraction for model development. Performance of MDI is then compared to the amplitude spectrum area (AMSA) technique. Results 358 defibrillations were evaluated (218 unsuccessful and 140 successful). Non-linear properties (Lyapunov exponent \u3e 0) of the ECG signals indicate a chaotic nature and validate the use of novel non-linear dynamic methods for feature extraction. Classification using MDI yielded ROC-AUC of 83.2% and accuracy of 78.8%, for the model built with ECG data only. Utilizing 10-fold cross-validation, at 80% specificity level, MDI (74% sensitivity) outperformed AMSA (53.6% sensitivity). At 90% specificity level, MDI had 68.4% sensitivity while AMSA had 43.3% sensitivity. Integrating available end-tidal carbon dioxide features into MDI, for the available 48 defibrillations, boosted ROC-AUC to 93.8% and accuracy to 83.3% at 80% sensitivity. Conclusion At clinically relevant sensitivity thresholds, the MDI provides improved performance as compared to AMSA, yielding fewer unsuccessful defibrillations. Addition of partial end-tidal carbon dioxide (PetCO2) signal improves accuracy and sensitivity of the MDI prediction model

Biochemical and electrophysiological markers predictive of return of spontaneous circulation and post-resuscitation outcome

The majority of patients resuscitated from cardiac arrest (CA) subsequently die due to post-cardiac arrest syndrome (PCAS), whose mechanisms are only partially understood. We adopted an approach of untargeted/targeted plasma metabolomics in rats to identify metabolites involved in the mechanisms of PCAS to be tested as predictors of outcome. Activation of the kynurenine pathway (KP) for tryptophan (TRP) degradation was demonstrated in rats, pigs and in a small cohort of patients. Decreases in TRP occurred during the post-CA period and were accompanied by significant increases in KP metabolites, 3-hydroxyanthranilic acid (3 -HAA) and kynurenic acid in each species, that persisted up to 3-5 days post-CA (p<0.01). KP metabolites changes were significantly related to the severity of myocardial and cerebral injuries and survival. Finally, when tested in 155 patients resuscitated from CA, KP metabolites were significantly higher in patients with poor outcomes. The quality of chest compression (CC) is another major issue for cardiopulmonary resuscitation (CPR) success and survival. The decision whether to interrupt CC to deliver a defibrillation (DF) is difficult. The potential benefit of a DF guided by a real time ventricular fibrillation (YF) waveform analysis would maximize DF success, minimize CC interruptions and myocardial damage by repetitive and unnecessary DFs. We evaluated amplitude spectrum area (AMSA) as predictor of DF outcome in two large databases of out-of-hospital VFs, from US (609 patients) and Italy (1.617 patients). AMSA was significantly higher prior to a successful DF than prior to an unsuccessful one (p<0.0001). Thresholds for prediction of successful and unsuccessful DFs were 16-17 mV-Hz for success and <7 mV-Hz for failure, with a positive predictive value of 80% and a negative predictive value of 97%. AMSA was a better predictor of DF outcome (AUC 0.86, p<0.0001) compared to other VF parameters, i.e. amplitude and frequencies. In conclusion, AMSA would be a useful tool for guiding CPR

High Resolution Multi-parametric Diagnostics and Therapy of Atrial Fibrillation: Chasing Arrhythmia Vulnerabilities in the Spatial Domain

After a century of research, atrial fibrillation (AF) remains a challenging disease to study and exceptionally resilient to treatment. Unfortunately, AF is becoming a massive burden on the health care system with an increasing population of susceptible elderly patients and expensive unreliable treatment options. Pharmacological therapies continue to be disappointingly ineffective or are hampered by side effects due to the ubiquitous nature of ion channel targets throughout the body. Ablative therapy for atrial tachyarrhythmias is growing in acceptance. However, ablation procedures can be complex, leading to varying levels of recurrence, and have a number of serious risks. The high recurrence rate could be due to the difficulty of accurately predicting where to draw the ablation lines in order to target the pathophysiology that initiates and maintains the arrhythmia or an inability to distinguish sub-populations of patients who would respond well to such treatments. There are electrical cardioversion options but there is not a practical implanted deployment of this strategy. Under the current bioelectric therapy paradigm there is a trade-off between efficacy and the pain and risk of myocardial damage, all of which are positively correlated with shock strength. Contrary to ventricular fibrillation, pain becomes a significant concern for electrical defibrillation of AF due to the fact that a patient is conscious when experiencing the arrhythmia. Limiting the risk of myocardial injury is key for both forms of fibrillation. In this project we aim to address the limitations of current electrotherapy by diverging from traditional single shock protocols. We seek to further clarify the dynamics of arrhythmia drivers in space and to target therapy in both the temporal and spatial domain; ultimately culminating in the design of physiologically guided applied energy protocols. In an effort to provide further characterization of the organization of AF, we used transillumination optical mapping to evaluate the presence of three-dimensional electrical substrate variations within the transmural wall during acutely induced episodes of AF. The results of this study suggest that transmural propagation may play a role in AF maintenance mechanisms, with a demonstrated range of discordance between the epicardial and endocardial dynamic propagation patterns. After confirming the presence of epi-endo dyssynchrony in multiple animal models, we further investigated the anatomical structure to look for regional trends in transmural fiber orientation that could help explain the spectrum of observed patterns. Simultaneously, we designed and optimized a multi-stage, multi-path defibrillation paradigm that can be tailored to individual AF frequency content in the spatial and temporal domain. These studies continue to drive down the defibrillation threshold of electrotherapies in an attempt to achieve a pain-free AF defibrillation solution. Finally, we designed and characterized a novel platform of stretchable electronics that provide instrumented membranes across the epicardial surface or implanted within the transmural wall to provide physiological feedback during electrotherapy beyond just the electrical state of the tissue. By combining a spatial analysis of the arrhythmia drivers, the energy delivered and the resulting damage, we hope to enhance the biophysical understanding of AF electrical cardioversion and xiii design an ideal targeted energy delivery protocol to improve upon all limitations of current electrotherapy

Safety and efficacy of elective cardioversion in atrial fibrillation the FinCV studies

Background: Major gaps exist in the evidence for predicting optimal patient outcomes of cardioversion (CV) in atrial fibrillation (AF). The aim of this dissertation was to assess the safety and efficacy of elective CV in AF. Methods: The Finnish Cardioversion study programme (FinCV) investigates the occurrence of stroke and procedural efficacy in AF patients undergoing CV. Studies included patients undergoing acute CV (FinCV), elective CV in vitamin K antagonist treated patients (FinCV2) and non-vitamin K antagonist treated patients (Fin-CV3). The patients' data were retrospectively collected during the 2003–2016 timeframe from nine Finnish hospitals. Altogether, the FinCV studies comprised 5441 patients and 10852 CVs, of which the FinCV2 study encompassed 1342 patients with 1998 elective CVs. Results: Elective CV was unsuccessful or AF recurred within the 30-day follow-up after an initially successful CV in 42.6% (FinCV2). Altogether, 6 (0.4%) cerebral thromboembolisms were detected within follow-up and patients with low (2.0–2.4) therapeutic internationalized normalized ratios (INRs) at the time of elective CV had a higher risk for thromboembolic events than patients with high (≥2.5) therapeutic INRs (0.9% vs. 0.1%, p=0.03) (FinCV2). In the combined registry of the FinCV studies the primary composite end-point was designated as an occurrence of death, thromboembolism, unsuccessful CV, recurrence of AF or acute arrhythmic complication within follow-up. The composite adverse outcome was observed after 1669 (38.4%) CVs and patients with AF episodes lasting 24–48 hours had the lowest risk of adverse outcomes. Conclusions: The intensity of anticoagulation in elective CV of AF is associated with the risk of postprocedural thromboembolisms. Nevertheless, CV in AF has relatively few safety issues, although more room exists for improvement in efficacy outcomes of CV in contemporary medicine.Eteisvärinän elektiivisen kardioversion turvallisuus ja tehokkuus – Fincv-tutkimukset Tausta: Vaikka rytminsiirto on keskeisin toimenpide eteisvärinän palauttamisessa sinusrytmiin, tehokkaan rytminsiirron ennustetekijöistä on vain vähän tietoa. Tämä väitöskirja selvittää eteisvärinän elektiivisen kardioversion turvallisuuden ja tehokkuuden ennustetekijöitä. Menetelmät: FinCV-tutkimukset ovat osa retrospektiivistä rekisteritutkimusohjelmaa, jossa selvitetään eteisvärinän kardioversioon liittyvää aivoinfarkti- ja verenvuotoriskiä. Potilasaineisto kerättiin vuosien 2003 – 2016 aikana yhdeksästä suomalaisestsa sairaalasta. Tutkimukset sisältävät yhteensä 5441 potilasta ja 10852 kardioversiota, joista FinCV2-tutkimukseen kuuluu 1342 potilasta ja 1998 elektiivistä kardioversiota. Tulokset: FinCV-tutkimuksien yhdistelmäaineistossa ensisijainen yhdistelmäpäätetapahtuma,johon sisältyi rytminsiirron epäonnistuminen, eteisvärinän uusiutuminen tai akuutti rytmihäiriökomplikaatio, verenkiertohäiriön ilmaantuminen tai kuolema 30 päivän seuranta-ajan sisällä, ilmeni 1669 (38.4 %) rytminsiirrossa. Potilailla, joiden eteisvärinäkohtauksen kesto oli 24 – 48 tuntia, oli kaikkein vähiten haittatapahtumia. Toisaalta elektiivinen rytminsiirto epäonnistui tai eteisvärinä uusiutui 30 päivän seurantaajan kuluessa 42.6 % toimenpiteistä. Aivoverenkiertohäiriöitä todettiin vähän 0.4 % FinCV2-tutkimusaineistossa 30 päivän seuranta-ajan kuluessa ja niillä potilailla, joilla rytminsiirtohetkellä INR-arvo oli 2.0 – 2.4, oli korkeampi aivoverenkiertohäiriöriski kuin potilailla, joiden INR-arvo oli ≥ 2.5 rytminsiirtohetkellä (5/529 (0.9 %) vs. 1/895 (0.1 %), p = 0.03)

Frequency Analysis of Atrial Fibrillation From the Surface Electrocardiogram

Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. Neither the natural history of AF nor its response to therapy are sufficiently predictable by clinical and echocardiographic parameters. Atrial fibrillatory frequency (or rate) can reliably be assessed from the surface electrocardiogram (ECG) using digital signal processing (filtering, subtraction of averaged QRST complexes, and power spectral analysis) and shows large inter-individual variability. This measurement correlates well with intraatrial cycle length, a parameter which appears to have primary importance in AF domestication and response to therapy. AF with a low fibrillatory rate is more likely to terminate spontaneously, and responds better to antiarrhythmic drugs or cardioversion while high rate AF is more often persistent and refractory to therapy. In conclusion, frequency analysis of AF seems to be useful for non-invasive assessment of electrical remodeling in AF and may subsequently be helpful for guiding AF therapy

ECG waveform dataset for predicting defibrillation outcome in out-of-hospital cardiac arrested patients

The provided database of 260 ECG signals was collected from patients with out-of-hospital cardiac arrest while treated by the emergency medical services. Each ECG signal contains a 9 second waveform showing ventricular fibrillation, followed by 1 min of post-shock waveform. Patients’ ECGs are made available in multiple formats. All ECGs recorded during the prehospital treatment are provided in PFD files, after being anonymized, printed in paper, and scanned. For each ECG, the dataset also includes the whole digitized waveform (9 s pre- and 1 min post-shock each) and numerous features in temporal and frequency domain extracted from the 9 s episode immediately prior to the first defibrillation shock. Based on the shock outcome, each ECG file has been annotated by three expert cardiologists, - using majority decision -, as successful (56 cases), unsuccessful (195 cases), or indeterminable (9 cases). The code for preprocessing, for feature extraction, and for limiting the investigation to different temporal intervals before the shock is also provided. These data could be reused to design algorithms to predict shock outcome based on ventricular fibrillation analysis, with the goal to optimize the defibrillation strategy (immediate defibrillation versus cardiopulmonary resuscitation and/or drug administration) for enhancing resuscitation. © 202

New Paradigm of Defibrillation: Towards Painless Therapy

Sudden cardiac death: SCD) causes approximately 300,000 - 400,000 deaths a year in the United States. It usually starts as ventricular tachycardia: VT) and then degenerates into ventricular fibrillation: VF). Implantable cardioverter defibrillator: ICD) therapy is the only reliable treatment of VT/VF and has been shown to effectively reduce mortality by many clinical trials. However, high-voltage ICD shocks could result in myocardial dysfunction and damage. The majority of patients receiving ICD therapy have a history of coronary disease; their hearts develop myocardium infarction, which could provide a substrate for reentrant tachy-arrhythmias. Other than lethal ventricular tachycardia, atrial fibrillation: AF) became the most common arrhythmia by affecting 2.2 to 5.6 millions of Americans. The complications of AF include an increased rate of mortality, heart failure, stroke, etc. In this dissertation, we explore mechanisms of sustained ventricular and atrial tachyarrhythmias and the mechanisms of defibrillation using the conventional high-voltage single shock. Through the use of novel fluorescent optical mapping techniques and several animal models of ventricular and atrial arrhythmias, we develop and validate several novel low-voltage defibrillation therapies for atrial and ventricular arrhythmias. Several important previous studies on mechanisms of arrhythmia maintenance and termination using mathematical and experimental models are overviewed in Chapter 2. A study on multiple monophasic shocks improving electrotherapy of ventricular tachycardia in rabbit model of chronic infarction is presented in Chapter 3. Ventricular arrhythmias and low-voltage defibrillation therapy are studied in a more clinically-relevent in vivo canine model of healing myocardial infarction in Chapter 4. Finally, Chapter 5 presents a novel multi-stage low-energy defibrillation therapy for atrial fibrillation in in vivo canine hearts

Improving Outcome After Cardiac Arrest: New Pharmacological And Electrophysiological Approaches During Cardiopulmonary Resuscitation

Cardiac arrest (CA) represents a leading cause of death in the western world. CA is a dramatic clinical event that can occur suddenly and often without premonitory signs. This condition is characterized by sudden loss of consciousness caused by the lack of cerebral blood flow, which occurs when the heart ceases to pump. Chest compressions (CCs) and early defibrillation (DF) are the cornerstones of cardiopulmonary resuscitation (CPR) in CA, while the only definitive treatment for ventricular fibrillation (VF) remains prompt DF. The present thesis includes both experimental and clinical studies directed to evaluate new pharmacological and electrophysiological approaches that have a potential benefit in the outcome of patients affected from CA. In order to achieve such aims, we performed two separate studies concurrently. The first study was directed to investigate experimentally the role of β1-blockade during CPR, while the second series of study evaluated prospectively the feasibility of a real time VF waveform analysis, in particular Amplitude Spectrum Area (AMSA), to guide interventions during resuscitation and to potentially diagnose underlying cardiac ischemia. Both the studies therefore concurred to the same goal of identify new tools to improve the outcome of CA and are presented together in this thesis as a single study with an introduction, methods, results, and discussion section. Nevertheless, in order to help the readers going throughout the work, each section is divided into sub-sections presenting separately the studies