Extracellular Matrix Marker of Arrhythmia Risk (EMMA)

Sudden cardiac death (SCD) is responsible for 300,000-450,000 deaths per year in the United States. While it is well known that patients with both ischemic and non-ischemic cardiomyopathy (ICM, NICM) are at increased risk for SCD, there is little beyond ejection fraction which has proven useful as a noninvasive predictor to risk stratify these patients.

Myocardial scar has been validated as an arrhythmic substrate in ischemic populations; the majority of successful ablations for lethal ventricular arrhythmias are performed on tissues in peri-infarct regions. Scar provides an anatomic electrical boundary where peri-infarct zones may lead to areas of slow conduction due to the disruption of inter-myocyte electrical conduction.

Myocardial scar is a less organized collagen deposition which disrupts the typical cardiac extracellular matrix. The collagen matrix provides mechanical support to the myocardium dictating ventricular shape, size and stiffness. While typically relatively dormant, the fibrillar collagen matrix reflects a dynamic relationship between collagen synthesis mediated by fibroblasts and collagen degradation performed by matrix metalloproteinases (MMP).

A marker for scar burden or a marker which could assess a patient's predilection to form scar after either an ischemic or non-ischemic insult may be useful in further risk stratifying this population. Since MMP levels may fluctuate in the course of ischemic or nonischemic injury a static promoter sequence which confers a higher level of MMP expression to an ischemic or nonischemic insult may prove to be a reliable marker. Functional polymorphisms of the MMP-9 gene promoters have been shown in multivariate analysis to be an independent predictor of cardiac mortality regardless of the mechanism of heart failure.

Inclusion criteria

• LVEF of ≤ 35% measured within 6 months of ICD implantation
• NYHA class II-IV at the time of ICD implantation
• ICD implantation at least 1 year prior to enrollment

Exclusion criteria

• Status post heart transplant
• Known malignancy in the past 2 years.
• Recent procedure, intervention or surgery within the past 90 days
• Acute MI, CABG, or PTCA/stent within the past 2 months.
• Active rheumatoid arthritis or pulmonary or hepatic fibrosis.
• Taking chronic steroid therapy for a medical condition
• Currently pregnant
• Enrolled in a concurrent study that may confound the results of this study