Prognosis Impact of NSVTs After an AMI (TeVeO Study).
Prognosis Impact of NSVTs After an AMI (TeVeO Study).
Nowadays, Sudden Cardiac Death (SCD) due to malignant arrhythmias is an important cause of
 death among acute myocardial infarction (AMI) survivors. Preventive strategies with
 implantable cardioverter-defibrillators (ICD) are the best clinical option for patients, but
 associated sociosanitary impact in the National Health Systems and the fact that current
 implant strategy not always results in benefits for the patient requires to develop further
 selection criteria. The TeVeO project aims to study the events that take place early
 following an AMI to predict the short- and long-term risk of experiencing a potentially
 lethal ventricular tachycardia (VT). The project will carry out an observational and
 multicentric study involving 5 different hospitals to: a) qualitative and quantitative
 characterize non-sustained VTs (NSVT) that take place during the first 6 months after an AMI
 and b) characterize the evolution of the substrate (scar and surrounding tissue) in patients
 meeting criteria for ICD implant. Patients included in the study will be implanted with an
 implantable loop recorder (ILR) in order to register NSVT and cMRI images will be acquired
 prior to hospital discharge and at 6 months after AMI to study the substrate. Further
 patients' management will follow the protocols within each entity. Project results will allow
 us to stratify patients according to identified risks for developing malignant VT, which will
 improve patient selection for ICD implantation and will contribute to tailor patients'
 treatment and prevention, improving the cost-effectiveness of these devices and minimizing
 their associated problems and sociosanitary burden.
INTRODUCTION Worldwide, cardiovascular diseases (CVD) are the leading cause of death, being
 responsible for nearly one out of three demises, and including pathologies with a huge impact
 in patients' and their families' quality of life and a major sociosanitary burden for
 national health systems. Among them, ischemic heart diseases including mainly myocardial
 infarction are the leading cause of death (12-15% deaths Globally), but with significative
 differences among countries. In Spain, and similarly in other European nations, prevention
 strategies, early and new therapeutic interventions and social awareness campaigns have
 contributed to reduce ischemic heart diseases death rate from 11% in 2001 to 7.6%. However,
 its incidence has remained practically unaltered in last decades due to the fact that the
 benefit from prevention strategies is being undermined by progressive population ageing.
 Since elder patients are at higher risk of developing these cardiovascular diseases, the
 impact and burden of heart failure in our society are expected to be increased during the
 next decades. Nowadays, approximately 30% of the patients with an acute myocardial infarction
 (AMI) die before reaching the hospital. Among survivors, life-threatening sequels are highly
 common and account for secondary alterations in heart pacing, mainly ventricular tachycardia
 (VT), and contractility leading to heart failure. VT can be also presented as a consequence
 of other pathologies, but cardiac alteration following AMI is the underlying cause in most
 patients and it is often poorly tolerated leading to sudden cardiac death (SCD) in up to 30%
 of AMI survivors. Today SCD represents a relevant problem for national health systems and it
 is expected to get worse in the future European society due to population aging.

 According to the duration of the episodes, VT can be classified as non-sustained, when the
 altered rhythm is selfterminated within 30 seconds, and sustained if it lasts more than 30
 secs. While non-sustained VT (NSVT) are frequently asymptomatic, sustained VT (SVT) are
 potentially lethal leading to SCD by haemodynamic destabilization, shock or ventricular
 fibrillation and usually an intervention is required to stop the arrythmia.

 Interventions to avoid SCD following SVT are based on restoring sinus rhythm as soon as
 possible. Therefore, preventive strategies with implantable cardioverter-defibrillator (ICD)
 are the best clinical option for certain patients at higher risk of developing VT leading to
 life-threating events and, in fact, its implantation can rescue them from SCD. Some patients
 more prone to suffer STV following AMI are those with prior history of SVT, poorly tolerated
 VT or previous aborted SCD. Prevention of further lethal VT by ICD implantation, a strategy
 known as secondary prevention, was proved beneficial by through 3 different early clinical
 trials, even when compared with antiarrhythmic drugs. The overall evidence clearly
 demonstrated that IDC reduce global and arrhythmic death and thus, its implantation is now a
 class I recommendation in the international guidelines for patients with aborted SCD, or
 potentially lethal VT. On the other hand, despite the fact that NSVT are usually
 asymptomatic, they often precede SVT especially when recurrent and monomorphic as an
 expression of a significant ventricular dysfunction. These NSVT are the clinical
 manifestation of an underlaying arrhythmogenic substrate and of the activation status of
 triggering factors. In fact, our group has published that the amount of NSVT is associated
 with the risk of medium and long-term clinically relevant events, especially with the risk of
 developing poorly tolerated and potentially lethal VT. Several multicentric prospective
 clinical studies have demonstrated that ICD implantation improves overall survival of
 patients at high risk of developing a first episode of SVT after AMI, a strategy known as
 primary prevention. As a general conclusion, mortality is reduced around 20-30% and mainly
 due to SCD abortion. Although different approaches have been considered to identify those
 patients at higher risk, up to date, scientific evidence only support selection of ICD
 candidates for primary prevention according to following criteria: a) left ventricular
 ejection fraction (LVEF) and b) functional class by the New York Heart Association (NYHA)
 scale, both measured between 1-6 months after the AMI and under optimal pharmacological
 treatment with antiarrhythmic drugs. However, different guidelines do not agree on LVEF
 threshold to select primary ICD implantation, but it is generally accepted that a benefit is
 obtained in patients with functional class I-III and LVEF<35%.

 However, ICD devices not always produce benefits. On one hand, the apparition of a lethal SVT
 is not prevented, just aborted, and ICD implantation early after AMI is not translated into a
 better prognostic outcome for the patient. In fact, in the MADIT-II study, ICDs only produced
 a reduced mortality in patients implanted beyond 18 months after AMI. On the other, the
 device only responses to treat a VT in one every 10 patients implanted for primary
 prevention. Besides, ICD implantation requires an invasive surgery which implies the
 possibility of having a surgical complication and post-procedural infections in up to 3% of
 the patients, requiring sometimes to remove the IDC and replace it once the infection is
 cleared up. IDC malfunction and inappropriate shocks delivered by the device when no
 life-threatening arrythmia is present are additional problems that can be presented after the
 surgery. Therefore, device implantation and management accounts for a high economic cost,
 with a relevant burden for the national health systems and, despite the fact that clear
 benefits are observed, patient selection for primary prevention of VT by IDC implantation
 should be further studied in order to first maximize the cost-effectiveness of the device and
 second minimize as much as possible associated complications and sociosanitary burden.

 Implantable loop recorders (ILR) are small devices that are subcutaneously implanted
 requiring a minimally invasive procedure and work as a long-term Holter, monitoring for
 24-hour a day patient's heart rhythm to detect arrythmias. ILR are compatible with remote
 monitoring systems (RMS), allowing the patients to send daily the information registered by
 the device to the healthcare center just using a conventional phone landline. This
 information can be immediately analyzed by the medical practitioner allowing to quickly adopt
 proper measures according to patient's clinical situation, which contributes to reduce the
 morbidity and mortality. Due to their safety and effectiveness, ILR are a valuable tool for
 the diagnosis of different clinical manifestations suspected to have a cardiac origin.
 However, up to date they have not been systematically used to detect NSVT in patients
 following an AMI, neither in their prognostic stratification, thus the viability of this
 strategy that could result in improving patients selection for ICD implantation need to be
 demonstrated. Though ILR monitoring, the TeVeO project aims to qualitative and quantitative
 characterize NSVT that take place during the first 6 months after an AMI, stablishing the
 relative importance of the two main factors influencing the arrhythmogenic mechanisms that
 can originate potentially lethal VT: substrate and triggers, which will allow us to advance
 in the proper treatment and prevention of these life-threatening events through patients
 stratification. The substrate for VT following AMI is the scar tissue, which extension and
 heterogeneity increase the risk. Prior studies have demonstrated that scar characterization
 by cardiac magnetic resonance imaging (cMRI) provides additional information to the LVEF and
 functional class to identify those patients at higher arrhythmic risk. However, little data
 are available regarding the underlying substrate and its evolution in chronic AMI with NSVT.
 Therefore, in addition to ILR monitoring, TeVeO study will evaluate the scar tissue by cMRI
 trying to identify further predictive markers associated to increased risk of developing SVT
 after AMI.

 HYPOTHESIS The project is grounded on the main assumption that the unsustained ventricular
 tachycardias (NSVT) that spontaneously occur during the first 6 months after an AMI can
 predict short and long-term functional outcome, specifically the risk of experiencing a
 potentially lethal VT. Therefore, the study of theses arrhythmic events can contribute to
 patient stratification and help to develop further improvements for their management.

 TeVeO project assume the following further hypothesis for the study of the NSVT following an
 AMI:

 -  The implantable loop recorders (ILRs) are able to accurately detect the NSVTs that
 patients submitted to coronary revascularization experiment after the medical discharge
 and during the first 6 months after an acute myocardial infarction (AMI).

 -  There are differences in the arrhythmogenic substrate of patients presenting NSVT in the
 6 first months after an AMI with depressed left ventricular ejection fraction (LVEF)
 that can be determined by the study of the scar tissue by cardiac MRI (cMRI).

 OBJECTIVES The main objective of TeVeO study is to qualitative and quantitative characterize
 NSVTs that take place during the first 6 months after an AMI in patients with LVEF ≤40%, and
 to discriminate the short- and long-term risks of developing potentially lethal arrhythmic
 events, which will contribute to tailor patients' treatment and prevention according to
 identified risks and will improve patient selection for implantable
 cardioverter-defibrillator (ICD) implantation, improving the cost-effectiveness of these
 devices and minimizing its associated problems and sociosanitary burden.

 To achieve main purpose, primary and secondary specific objectives have been stablished.

 METHODS.

 1. Characteristics:

 Type: prospective clinical study, multicentric, Observational study. Participating
 centres: Hospital Universitario de Salamanca, Complejo Asistencial Universitario de
 Burgos, Hospital Universitario San Pedro de Alcántara, Complejo Asistencial
 Universitario de Santiago de Compostela and Complejo Asistencial Universitario de Lugo.

 Comparing groups: Acquired data within the first 6 months after an AMI will be study in
 order to stablish possible associations with the patient outcome in the first 2 years
 after an AMI.

 Definitions:

 -  NSVT: Any rhythm with a wide QRS from a ventricular origin that is self-terminated
 within 30 second, with a heart rate over 100 bpm and over 5 beats.

 -  SVT: Any rhythm with a wide QRS from a ventricular origin with a heart rate over
 100 bpm, that lasts over 30 seconds or that needs an intervention to be finished.

 -  Monomorphic VT: All QRS complex present the same morphology

 -  Polymorphic VT: QRS morphology changes in any heartbeat.

 -  Appropriate therapy: Any therapy (antitachycardia pacing or discharge) applied by
 ICD due to a ventricular tachycarrhythmia.

 -  Inappropriate therapy: Any ICD therapy that is not due to a ventricular
 tachycarrhythmia.

 -  Ischemic left ventricular dysfunction: The systolic dysfunction due to a previous
 coronary artery disease with myocardial necrosis with previous demonstration of at
 least one obstructed epicardial coronary artery, and presence of ischemic scar in
 MRI with characteristic distribution of late-enhancement of gadolinium.

 2. Study population: Unselected patients who have suffered a myocardial infarction and who
 have an LVEF equal to or less than 40% (determined by transthoracic echocardiography) on
 the fourth day after the event.

 Sample size calculation: Study aims to include around 200 AMI patients. Sample size has
 been estimated for a confidence level of 95%, defined by a coefficient Za = 1.96 and
 taking into account a prevalence (p) of NSVT (< 5 episodes in 6 months) of 15% and a
 precision level (d) of 5%. According to the following formula, in which q = 1-p:

 n = Z2 * a * p * q / d2 n = 3.84 * 0.15 * 0.85 / 0.0025 = 196 patients to be included.

 3. Study design:

 -  Epidemiological and basic clinical data of all the patients hospitalized in the
 participating hospitals after an episode of AMI will be collected.

 -  Patients accomplishing inclusion and exclusion criteria will be submitted to
 continuous electrocardiographic monitoring until medical discharge.

 -  Before discharge a cMRI (days 6-10 after AMI) will be performed and after an ILR
 will be implanted.

 -  Following medical discharge, enrolled patients will daily transmit the device
 register, which will be analyzed by specialized personnel. An intervention will
 take place if any arrhythmic event is registered following the current
 recommendations of scientific society.

 -  Patients will be reevaluated 6 months after the coronary revascularization
 performed during hospitalization. This clinical evaluation will include, at least,
 the clinical and functional status (NYHA scale), pharmacological treatment and LVEF
 determination by echocardiography. Besides, ILR will be explanted to cMRI
 acquisition. If the patient fulfills current criteria of the European Society of
 Cardiology according to LVEF criteria, an ICD will be then implanted without
 resynchronization therapy. If the patient does not fulfill ICD criteria, ILR
 monitoring will continue for 18 months more (2 years after the AMI event). Periodic
 clinical checkup will take place according to the protocols specified by our
 center. According to the scientific evidence, 5-10% of subjects with LVEF <40% in
 the first week post revascularizated AMI will recover part of the ventricular
 function, falling outside of ICD implantation criteria.

 -  Patients will be followed-up during the first 2 years after the AMI. Periodic
 checkups will be programmed according to the protocols of our center. ICD and ILR
 implanted patients will daily transmit the device register that will be weekly
 reviewed.

 -  After the 2 years follow-up, the ILR, in those patients without an ILR, will be
 explanted and a cMRI will be performed.

 ICD programming:

 Detection and therapy programming will be standardized and included two zones:
 Ventricular Fibrillation (VF) (Cycle Length [CL] < 250 ms) and Ventricular Tachycardia
 Zone 1 (CL from 250 to 320 ms). In both cases tachycardia detection will require that 30
 of the last 40 R-R intervals had to have a CL bellow the cutoff point. Episodes
 classified as VF will receive a sequence of high-energy shocks. Otherwise, episodes
 detected in Ventricular Tachycardia Zone 1 will be initially treated by a single ATP
 sequence (an 8-pulse-burst train at 88%). Failed ATP will be followed by shock and then
 other shocks as necessary. An additional monitoring zone (Ventricular Tachycardia Zone
 2) will be programmed for episodes with a CL from 321 to 400 ms. All devices will be
 programmed to store the far-field electrograms before the onset of the episodes detected
 to aid in rhythm classification.

 MRI protocol:

 All patients will undergo contrast-enhanced MRI with a 1.5-T or 3 T scanner. All images
 will be obtained with electrocardiographic gating and breath-holding. The MRI study will
 consist of cine steady-state free precession imaging of left ventricular function and
 late enhancement imaging of myocardial scar tissue. Late Enhancement images will be
 obtained 10 to 15 min after an injection of 0.2 mmol/kg of gadodiamide. Late-enhanced
 images will be used for infarct characterization. Infarct and heterogeneous tissue
 (i.e., gray zone) mass will be quantified by 2 methods: 1) the full width at half
 maximum; and 2) on the basis of Standard Deviations (SD) of the signal intensity from
 the remote mean healthy myocardium (>2SDs defined the total infarct mass,>3SDs the core
 infarct and HT between 2 and 3 SDs).

 4. Data collection and statistical analysis

 Data collection:

 No personal data will be collected or processed without prior formal authorization. Once
 informed consent has been signed, data will be collected, stored and managed according
 to current local, national and EU legislation on this matter. In particular, the
 Regulation (EU) 2016/679 of the European Parliament and of the Council on the protection
 of natural persons with regard to the processing of personal data and on the free
 movement of such data will be carefully fulfilled. Any further ethical issue that may
 arise within the project will be properly consulted and addressed by participating
 entities.

 Clinical variables:

 1. Clinical variables from hospitalization phase:

 -  Date of AMI index.

 -  AMI location.

 -  Demographic data: age, gender, profession.

 -  Weight and height.

 -  Cardiovascular risk factors: Hypertension, dyslipemia, diabetes, smoking,
 obesity, peripheral vascular disease, drug abuse.

 -  Electrocardiographic variables:

 o Atrial rhythm (sinus, atrial fibrillation/flutter, paced).

 -  Number of Q waves.

 -  Duration of QRS complex.

 -  Presence of complete bundle branch block.

 -  Number of epicardial coronary arteries with stenosis >70%.

 -  Coronary revascularization: type (percutaneous and surgical) and affected
 arteries.

 -  NSVT incidence during hospitalization.

 -  LVEF measured 5-7 days following the AMI: %.

 -  Date of ILR implantation.

 -  Pharmacological treatment at medical discharge.

 2. Clinical variables from ILR monitoring phase:

 - Qualitative (heartbeats number, polymorphic/monomorphic) and quantitative (event
 number) incidence of NSVT.

 -  Functional Class (NYHA) and LVEF (by echo) 6 months after revascularization.

 -  Unplanned medical interventions as a consequence of data collected from the
 ILR within the 6 first months post-AMI.

 -  After six months of ILR monitoring, among non-appropriate patients for ICD
 implant, clinical events will be recorded: hospitalization due to cardiac
 causes, syncope, pacemaker of ICD implant, aborted SCD, cardiovascular death.

 3. Clinical variables from post-ICD implant phase:

 - ICD or ICD-TRC implant date.

 -  Complications related to ICD or ICD-TRC implant.

 -  Clinical events after ICD implant: appropriate therapies, appropriate
 discharges, inappropriate therapies, hospitalization due to heart failure,
 cardiovascular death.

 Variables from ILR recording:

 - Relevant arrhythmias: sinus pause >3 seconds, second- or third-degree AV block,
 NSVT, SVT.

 -  For NSVT:

 o Data: day and hour.

 o Number of beats.

 o Duration, seconds

 o Cycle Length.

 -  Morphology: monomorphic or polymorphic.

 -  For SVT:

 o Data: day and hour.

 o Duration, seconds.

 o Cycle Length.

 o Morphology: monomorphic or polymorphic.

 Variables from cMRI studies:

 - Left ventricular dimensions.

 -  LVEF.

 -  Extension of scar.

 -  Extension of dense scar.

 -  Extension of heterogeneous tissue.

 Statistical analysis:

 Statistical analysis will be performed using the SPSS programme 11.0 or further.
 Normal and continuous variables will be described by means and standard deviations,
 whereas categorical variables will be summarized by the number of patients and
 percentages. Comparison of the categorical variables will be performed with the
 Chi-square test (or Fisher's exact test if n<5). Comparison of 2 normal variables
 (determined with the Kolgomorov-Smirnov test) and continuous variables will be done
 with Student's t test. Comparison of >2 continuous variables will be performed
 using the ANOVA test. Multivariate analysis will be accomplished by a logistic
 regression or Cox regression tests. To determine the individual mean of proportions
 adjusted per multiple episodes per patient, the Generalized Estimating Equations
 Method will be used in the calculations and comparisons. A p value <0.05 will be
 considered statistically significant.

 Machine learning and Deep learning:

 Due to the great amount of data to be collected by the ILR during the first 6
 months after an AMI and by the ICD/ILR up to 2 years following the AMI, a Machine
 Learning analysis will be also performed to determine the association between the
 incidence, burden and temporal distribution of NSVTs registered by ILRs with the
 occurrence of ICD appropriate therapies.

 Machine Learning techniques to be used will consist in supervised since the
 response variable is identified. The usual algorithms (random forest, xgboost, SVM,
 etc.) will be combined in order to find the balance between bias and variance,
 avoiding overfitting the available data, so that the model can be successfully
 generalized to further populations. In cases where the response variable is
 represented by a few cases, we will use subsampling and oversampling techniques
 such as bagging balance. All the Machine Learning analysis will be carried out
 using the Python programming language and libraries like scikit-learn, which
 include proper algorithms and techniques for the project.

 Project will also acquire 2/3 cMRI of ICD/ILR implanted patients. Together with the
 abovementioned statistical analysis, cMRI images will be analyzed by deep learning
 (neural networks) in order to detect any possible pattern and their evolution. Raw
 images could be a reliable predictor of patient's evolution. For the implementation
 of deep learning techniques Keras and TensorFlow programs will be used.
Inclusion Criteria:

 -  AMI patients over 18 years old.

 -  LVEF equal or lower than 40% determined by a transthoracic echocardiography 4 days
 after the onset of the AMI.

 -  Revascularization during hospitalization according to the clinical practice guidelines

 -  Signed informed consent.

 Exclusion Criteria:

 -  Non-ischemic etiology of left ventricular dysfunction by cMRI.

 -  Patient already implanted with a cardiac device (pacemaker, ICD or ICD-TRC).

 -  Indication of pacemaker, ICD or ICD-TRC implantation during hospitalization.

 -  Allergy or hypersensitivity to any implatable device component.

 -  Contraindication for cMRI performance.

 -  Life expectancy under 1 year due to a non-cardiac cause.

 -  Concomitant valvulopathy with indication for surgery.

 -  High functional class (NYHA IV).

 -  No possibility to connect to the remote monitoring.