Despite pharmacologic advances for the treatment of congestive heart failure (HF), sudden cardiac death (SCD) and pump failure remain the leading causes of mortality in patients with HF. Although, SCD is poorly understood, implantable cardiac defibrillators (ICD) have been shown to be an effective, but costly therapy in preventing SCD. At present, left ventricular systolic dysfunction is our best independent predictor of SCD, but only moderately predicts those patients who will eventually benefit from the placement of an ICD and, in most cases, left ventricular (LV) systolic dysfunction is a non-modifiable risk factor once acquired. As a result, there exists an intensive search for biomarkers that could improve the prediction of SCD and have the potential for risk factor modification. Experimental and clinical evidence has established that inflammation plays a critical role in stable coronary disease, plaque rupture, acute myocardial infarction, heart failure, and SCD. Studies at our institution have demonstrated that elevated levels of hsCRP and Interleukin-6 are predictive of arrhythmic SCD;however, the mechanism of causing this increased risk is unclear. Another well-known risk factor for SCD is abnormal sympathetic innervation. The most robust clinical test of sympathetic innervation to date is Iodine-123 Metaiodobenzylguanidine (MIBG) imaging with gamma scintigraphy. MIBG imaging has emerged as one of our strongest predictors of SCD by detecting sympathetic nervous system abnormalities in patients with HF. Preclinical and clinical evidence suggests that myocardial inflammation adversely affects myocardial innervation. Based on these findings, we first hypothesize that elevated levels of inflammatory biomarkers are associated with abnormal sympathetic innervation as measured by MIBG imaging.
We aim to establish the strength of this association with the second goal of investigating whether modification of inflammatory biomarkers can improve sympathetic innervation and thus reduce the risk of SCD. This proposal will leverage unique access to the largest, most extensively phenotyped cohort of patients who have undergone ICD implantation for primary prevention of SCD, the PRospective Observational Study of the ICD in SCD, (PROSE-ICD).

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Studies have demonstrated that increased levels of serum protein biomarkers of inflammation are an independent predictor of arrhythmic sudden cardiac death (SCD). Preclinical and clinical studies suggest that inflammation has adverse consequences on cardiac sympathetic innervation and that this effect may be modified by therapies that that reduce inflammation. This proposal aims to establish the association between inflammation and abnormal sympathetic innervation measured by Iodine-123 Metaiodobenzylguanidine (MIBG) imaging, a known risk predictor for arrhythmic SCD, and test the hypothesis that modification of inflammation can improve sympathetic innervation to the heart.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Exploratory/Developmental Grants (R21)
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Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
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Lathrop, David A
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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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George, Richard T; Mehra, Vishal C; Saraste, Antti et al. (2012) Myocardial perfusion by CT versus hybrid imaging. Cardiol Clin 30:135-46