Clinical trial NCT02045043: Genetic Risk Assessment of Defibrillator Events
Official title: Genetic Risk Assessment of Defibrillator Events: A Prospective Multicenter Observational Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Sudden Cardiac Death
Arrhythmias
Congestive Heart Failure
Cardiomyopathy
Keywords: Sudden Cardiac Death
Arrhythmias
Congestive Heart Failure
Cardiomyopathy
Single Nucleotide Polymorphisms
Genomics
Lead sponsor: University of Iowa
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2014-01-24
Enrollment: 1807
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Shock-Free Survival
timeFrame: Up to 5 years
Secondary outcomes:
measure: Survival
timeFrame: Up to 5 years
measure: Transplant- and VAD-Free Survival
timeFrame: Up to 5 years
measure: Appropriate Shock Frequency
timeFrame: Up to 5 years
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Boston
country: United States
facility: Massuchetts General Hospital
state: Massachusetts
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
city: Columbus
country: United States
facility: Mid Ohio Cardiology
state: Ohio
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Pittsburgh
country: United States
facility: VA Pittsburgh Healthcare System
state: Pennsylvania
Study officials:
affiliation: University of Iowa
name: Barry London, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.