Arrhythmic Risk Stratification in Nonischemic Dilated Cardiomyopathy: The ReCONSIDER Study. A Two-step, Multifactorial, Electrophysiology-inclusive Approach

1. Study hypothesis There is an urgent need for reconsidering risk stratification approaches to DCMP patients, in addition to LVEF in order to identify subgroups at high arrhythmic risk that could benefit from ICD. This task could be achieved either by imaging and/or noninvasive, ECG-related, risk stratification techniques. In this direction, the investigators recently introduced a two-step multifactorial, noninvasive ECG findings leading to programmed ventricular stimulation (PVS), electrophysiology study (EP)-inclusive approach, to modify and protect the truly high risk post-myocardial infarction (MI) CAD patients with a LVEF≥40%. Based on the fact that those DCMP patients inducible on PVS into sustained ventricular tachycardia/fibrillation (VT/Vf) are the ones most likely to receive appropriate ICD therapy regardless of the degree of left ventricular contractile dysfunction or/and the presence of complex ventricular ectopy, the investigators now propose a similar two-step, multifactorial, noninvasive, EP-inclusive approach among the DCMP population with either relatively preserved (35%<LVEF≤50% - Group A) or reduced (LVEF≤35% - Group B) ventricular systolic function. The kernel of this approach lies in the premise that NIRFs detect arrhythmogenic potential and invasive PVS ascertains whether it translates to clinical arrhythmogenesis, combining the formers' sensitivity with the latter's specificity.

It is hypothesized that this approach will lead to i. Detection of a high risk subgroup among DCMP patients with 35%<LVEF≤50% that would benefit from an ICD in terms of total mortality (given that their non-SCD mortality component is low as they are at early heart failure stages with relatively preserved systolic function) ii. Stratification of the cohort with LVEF≤35% into clearly discernible arrhythmic risk level groups, with patients in the lowest one having a total mortality mostly due to heart-failure related death and potential ICD advantages negated by potential complications. 2. Population and methods ReCONSIDER is a multicenter, prospective observational trial, aiming to enroll DCMP patients in 17 major electrophysiology centers in Greece. Reimbursement for all devices will be provided by the Hellenic State. The study is under the auspices of the Hellenic Cardiology Society, in whose secure servers the online patient database will be maintained. Inclusion and exclusion criteria are described in the relevant sections.

A. Endpoints i. Primary endpoint: Major arrhythmic event (MAE) occurrence (ICD activation ± sudden cardiac death ± sustained ventricular tachycardia/ventricular fibrillation) ii. Secondary endpoints: Mortality (all-cause and heart failure-related) - Heart failure-related hospitalization - Device related complications (including pocket and lead-related infections, as well as inappropriate therapies) B. Stratification and treatment i. NIRFs

Presence of the following NIRFs will be evaluated:

1. History of syncope and/or presyncope in the absence of prodromal symptoms typical of vagally-mediated events
2. LV end diastolic diameter >60mm on echocardiography
3. LGE presence (qualitative approach - dichotomous value)
4. >30 premature ventricular complexes/hour on 24-hour electrocardiography
5. Presence of non-sustained ventricular tachycardia on 24-hour electrocardiography
6. 2/3 positive criteria for late potentials, either conventional or modified43
7. QTc derived from 24-hour electrocardiography >440ms (men) or >450ms (women)44 according to the Fridericia formula from a signal recorded in 3 pseudo-orthogonal leads
8. Ambulatory T-wave alternans ≥65μV in 2 Holter channels20, 45
9. Standard deviation of normal RR intervals ≤75ms on ambulatory electrocardiography
10. Deceleration capacity ≤4.5ms and heart rate turbulence onset ≥0% and heart rate turbulence slope ≤2.5ms46 ii. Cardiac MRI protocol Cardiac MRI protocol will entail the following: All patients recruited will undergo cMRI in a 1.5 Tesla system. All sites of cMRI fulfil the requirements of expertise and equipment to be involved in the trial. Each participating centre has approval by their respective Ethics Committee. Analysis will be performed with dedicated computer software.