Genetic Risk Assessment of Defibrillator Events (GRADE)

Genetic Risk Assessment of Defibrillator Events: A Prospective Multicenter Observational Study

Arrhythmias remain a major health problem, causing at least 250,000 deaths annually in the United States. Pharmacological treatments often do more harm than good, and device therapies are limited by high cost and effects on quality of life. Ion channel mutations cause rare inherited arrhythmopathies, but account for only a small fraction of patients with life- threatening arrhythmias and sudden death. Most arrhythmias occur during myocardial ischemia, following myocardial infarction, and in patients with poor left ventricular (LV) function of any etiology. Aside from ejection fraction (EF), few clinically useful indicators to stratify the risk of sudden death have been identified. The role of subtle difference in ion channel expression and/or structure in predisposing patients to arrhythmias and modulating the risk of sudden death is unknown.

In this study, we are prospectively testing whether polymorphisms in ion channels and ion channel modifying genes are associated with arrhythmias in a population with internal cardioverter-defibrillators (ICDs) and poor LV function. We will test the hypothesis that functional polymorphisms in the coding sequences and promoter regions of cardiac genes (e.g. ion channels, beta-adrenergic receptors) predispose individuals to arrhythmias and /or heart failure progression.

We hope to identify genetic predictors for the common forms of sudden cardiac death. This would allow the identification of a subpopulation of heart failure patients that would benefit most from ICD placement.

Study Overview

• Status: Completed
• Conditions: Congestive Heart Failure; Sudden Cardiac Death; Cardiomyopathy; Arrhythmias

• Study Type: Observational
• Enrollment (Actual): 1807

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massuchetts General Hospital
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University
    • Columbus, Ohio, United States, 43214
      • Mid Ohio Cardiology
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh
    • Pittsburgh, Pennsylvania, United States, 15240
      • VA Pittsburgh Healthcare System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Subjects 18 years of age and over with a cardiomyopathy, an ejection fraction less than or equal to 30%, and an implantable cardioverter defibrillator

Description

Inclusion Criteria:

• An ICD placed during the last 5 years, or a planned ICD within 1 month
• Age 18 or older
• Left Ventricular Ejection fraction < or = 30%
• Ability to give informed consent

Exclusion Criteria:

• Patient refuses or is unable to give consent
• A life expectancy <6 months from a non-cardiac life threatening disease
• Ongoing Class IV heart failure symptoms despite treatment
• History of cardiac transplant or left ventricular assist device

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Cardiomyopathy patients with ICDs

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Shock-Free Survival	Time to first appropriate shock from an Implantable Cardioverter-Defibrillator	Up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival	Time to death from any cause	Up to 5 years
Transplant- and VAD-Free Survival	Time to occurence of death from any cause, cardiac transplantation, or Ventricular Assist Device placement (whichever comes first)	Up to 5 years
Appropriate Shock Frequency	The number of appropriate shocks per year	Up to 5 years

Collaborators and Investigators

• Sponsor: University of Iowa
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Barry London, MD PhD, University of Iowa

Publications and helpful links

General Publications

• Refaat MM, Lubitz SA, Makino S, Islam Z, Frangiskakis JM, Mehdi H, Gutmann R, Zhang ML, Bloom HL, MacRae CA, Dudley SC, Shalaby AA, Weiss R, McNamara DM, London B, Ellinor PT. Genetic variation in the alternative splicing regulator RBM20 is associated with dilated cardiomyopathy. Heart Rhythm. 2012 Mar;9(3):390-6. doi: 10.1016/j.hrthm.2011.10.016. Epub 2011 Oct 17.
• Blanco RR, Austin H, Vest RN 3rd, Valadri R, Li W, Lassegue B, Song Q, London B, Dudley SC, Bloom HL, Searles CD, Zafari AM. Angiotensin receptor type 1 single nucleotide polymorphism 1166A/C is associated with malignant arrhythmias and altered circulating miR-155 levels in patients with chronic heart failure. J Card Fail. 2012 Sep;18(9):717-23. doi: 10.1016/j.cardfail.2012.06.531. Epub 2012 Aug 9.
• Bloom HL, Shukrullah I, Veledar E, Gutmann R, London B, Dudley SC. Statins Decrease Oxidative Stress and ICD Therapies. Cardiol Res Pract. 2010;2010:253803. doi: 10.4061/2010/253803. Epub 2010 Mar 25.
• Aleong RG, Mulvahill MJ, Halder I, Carlson NE, Singh M, Bloom HL, Dudley SC, Ellinor PT, Shalaby A, Weiss R, Gutmann R, Sauer WH, Narayanan K, Chugh SS, Saba S, London B. Left Ventricular Dilatation Increases the Risk of Ventricular Arrhythmias in Patients With Reduced Systolic Function. J Am Heart Assoc. 2015 Jul 31;4(8):e001566. doi: 10.1161/JAHA.114.001566.
• AlJaroudi WA, Refaat MM, Habib RH, Al-Shaar L, Singh M, Gutmann R, Bloom HL, Dudley SC, Ellinor PT, Saba SF, Shalaby AA, Weiss R, McNamara DM, Halder I, London B; Genetic Risk Assessment of Defibrillator Events Investigators. Effect of angiotensin-converting enzyme inhibitors and receptor blockers on appropriate implantable cardiac defibrillator shock in patients with severe systolic heart failure (from the GRADE Multicenter Study). Am J Cardiol. 2015 Apr 1;115(7):924-31. doi: 10.1016/j.amjcard.2015.01.020. Epub 2015 Jan 15.

Study record dates

Study Major Dates

• Study Start: March 1, 2002
• Primary Completion (Actual): June 1, 2012
• Study Completion (Actual): June 1, 2012

Study Registration Dates

• First Submitted: January 22, 2014
• First Submitted That Met QC Criteria: January 22, 2014
• First Posted (Estimate): January 24, 2014

Study Record Updates

• Last Update Posted (Estimate): January 24, 2014
• Last Update Submitted That Met QC Criteria: January 22, 2014
• Last Verified: January 1, 2014

More Information

Terms related to this study

• Keywords: Cardiomyopathy; Genomics; Congestive Heart Failure; Sudden Cardiac Death; Arrhythmias; Single Nucleotide Polymorphisms
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Death, Sudden; Heart Arrest; Heart Failure; Death; Arrhythmias, Cardiac; Cardiomyopathies; Death, Sudden, Cardiac
• Other Study ID Numbers: GRADE; R01HL077398 (U.S. NIH Grant/Contract)