Diffuse myocardial fibrosis associates with incident ventricular arrhythmia in implantable cardioverter defibrillator recipients

Background Diffuse myocardial fibrosis (DMF) quantified by extracellular volume (ECV) may represent a vulnerable phenotype and associate with life threatening ventricular arrhythmias more than focal myocardial fibrosis. This principle remains important because 1) risk stratification for implantable cardioverter defibrillators (ICD) remains challenging, and 2) DMF may respond to current or emerging medical therapies (reversible substrate). Objectives To evaluate the association between quantified by ECV in myocardium without focal fibrosis by late gadolinium enhancement (LGE) with time from ICD implantation to 1) appropriate shock, or 2) shock or anti-tachycardia pacing. Methods Among patients referred for cardiovascular magnetic resonance (CMR) without congenital disease, hypertrophic cardiomyopathy, or amyloidosis who received ICDs (n=215), we used Cox regression to associate ECV with incident ICD therapy. Results After a median of 2.9 (IQR 1.5-4.2) years, 25 surviving patients experienced ICD shock and 44 experienced shock or anti-tachycardia pacing. ECV ranged from 20.2% to 39.4%. No patient with ECV<25% experienced an ICD shock. ECV associated with both endpoints, e.g., hazard ratio 2.17 (95%CI 1.17-4.00) for every 5% increase in ECV, p=0.014 in a stepwise model for ICD shock adjusting for ICD indication, age, smoking, atrial fibrillation, and myocardial infarction, whereas focal fibrosis by LGE and global longitudinal strain (GLS) did not. Conclusions DMF measured by ECV associates with ventricular arrhythmias requiring ICD therapy in a dose-response fashion, even adjusting for potential confounding variables, focal fibrosis by LGE, and GLS. ECV-based risk stratification and DMF representing a therapeutic target to prevent ventricular arrhythmia warrant further investigation. Condensed Abstract Analogous to heart failure and mortality outcomes, diffuse myocardial fibrosis (DMF) quantified by extracellular volume (ECV) may represent a more vulnerable phenotype for life-threatening ventricular arrhythmia than focal myocardial fibrosis. In patients referred for cardiovascular magnetic resonance, we identified 215 subsequently receiving implantable cardioverter defibrillators (ICD). After a median of 2.9 (IQR 1.5-4.2) years, 25 patients experienced ICD shock and 44 experienced shock or anti-tachycardia pacing. ECV associated with ICD therapy in Cox regression models. Focal fibrosis variables or global longitudinal strain did not. ECV-based risk stratification and DMF representing a therapeutic target to prevent ventricular arrhythmia warrant further investigation. ### Competing Interest Statement Dr. Miller received research support from Roche and Guerbet and serves as Scientific Advisor to Haya Therapeutics. Dr. Schelbert has accepted contrast material from Bracco Diagnostics for research purposes and serves as Scientific Advisor to Haya Therapeutics. Dr. Ugander is principal investigator on a research and development agreement regarding CMR between Siemens and Karolinska University Hospital. Dr. Saba has received research support from Boston Scientific. Dr. Cavalcante has received consulting fees from Boston Scientific, Medtronic and Abbott Vascular; and research grant support from Abbott Vascular, Edwards Lifesciences, Medtronic, Boston Scientific, Circle Cardiovascular Imaging and Medis. The remaining authors have nothing to disclose. ### Funding Statement Dr. Miller is funded by a Clinician Scientist Award (CS-2015-15-003) from the National Institute for Health Research, Manchester, UK. Dr. Wong was supported by American Heart Association Scientist Development grant (Dallas, TX) and Childrens Cardiomyopathy Foundation grant. Dr. Schelbert was supported by a grant from The Pittsburgh Foundation (PA), Grant M2009‐0068 to EBS; and an American Heart Association (Dallas, TX) Scientist Development grant (09SDG2180083) including a T. Franklin Williams Scholarship Award; funding provided by: Atlantic Philanthropies, Inc, the John A. Hartford Foundation, the Association of Specialty Professors, and the American Heart Association (Dallas, TX). Dr. Ugander was supported in part by grants from New South Wales Health, Heart Research Australia, and the University of Sydney. This work was also supported by Grant Number UL1-TR-001857 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research (Bethesda, MD). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Institutional Review Board at the University of Pittsburgh Medical Center approved the study, and all subjects provided written informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study may be available upon reasonable request to the authors * ATP : anti-tachycardia pacing CMR : cardiovascular magnetic resonance DMF : diffuse myocardial fibrosis ECV : extracellular volume Focal MF : focal myocardial fibrosis GLS : global longitudinal strain ICD : implantable cardioverter defibrillator LGE : late gadolinium enhancement SCD : sudden cardiac death