Inflammation, Cardiac Sympathetic Innervation, and Arrhythmic Sudden Death

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Brief Title

Inflammation, Cardiac Sympathetic Innervation, and Arrhythmic Sudden Death

Official Title

Inflammation, Cardiac Sympathetic Innervation, and Arrhythmic Sudden Death

Brief Summary

      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

      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

      Based on these findings, the investigators hypothesize that elevated levels of inflammatory
      biomarkers are associated with abnormal sympathetic innervation as measured by MIBG imaging.
      The investigators aim to establish the strength of this association. 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).

Detailed Description

      The primary aim is as follows:

      Primary Aim 1: Determine if inflammation is associated with abnormal cardiac sympathetic
      innervation in patients enrolled in the PROSE-ICD study.

      Rationale/Hypothesis: The investigators hypothesize that patients with increased biomarkers
      of systemic inflammation have abnormal cardiac sympathetic innervation as measured by MIBG

      Specifically the investigators will: Image 100 patients from the PROSE-ICD cohort, 50 each
      from the highest and lowest quartiles of hsCRP levels and determine whether patients with
      biomarker evidence of increased inflammation also have abnormal sympathetic innervation.

      In addition, the investigators will pursue the following secondary aims:

        1. Determine if inflammation, measured by IL-6, is associated with abnormal cardiac
           sympathetic innervation, measured by MIBG imaging, in patients enrolled in the PROSE-ICD

        2. Examine the association of CRP and MIBG with ICD therapies in PROSE-ICD.

        3. Compare several MIBG imaging metrics of sympathetic innervation, in addition to the late
           H/M ratio, including the early H/M ratio and the MIBG washout rate.

        4. Compare MIBG imaging to ECG metrics of sympathetic innervation.

        5. Examine the relationship between inflammation and regional myocardial innervation and
           rest myocardial perfusion using quantitative and qualitative SPECT imaging.
           Specifically, the investigators will aim to determine if inflammation is associated with
           perfusion/innervation mismatch.

Study Type


Primary Outcome

Determine if inflammation is associated with abnormal cardiac sympathetic innervation in patients enrolled in the PROSE-ICD study.

Secondary Outcome

 Determine if inflammation, measured by IL-6, is associated with abnormal cardiac sympathetic innervation, measured by MIBG imaging


Ischemic Cardiomyopathy

Study Arms / Comparison Groups

 Primary Prevention of Sudden Cardiac Death
Description:  No intervention will be administered. This is an observational study testing the association of inflammation and cardiac sympathetic innervation using I-123-MIBG gamma scintigraphy


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Estimated Enrollment


Start Date

March 2012

Completion Date

September 2014

Primary Completion Date

September 2014

Eligibility Criteria

        Patient Population - This proposal will enroll patients from the PROSE-ICD cohort who have
        undergone ICD implantation for primary prevention of SCD. PROSE-ICD is a multicenter
        prospective observational cohort study designed to identify risk factors for SCD in
        high-risk patients.

        Inclusion Criteria The entire PROSE-ICD population with ischemic and non-ischemic
        cardiomyopathy will be divided into quartiles based on previously measured hsCRP levels in
        the PROSE-ICD database. The study sample for this study will include 50 randomly selected
        PROSE-ICD participants from the lowest hsCRP quartile and another 50 randomly selected
        participants from the highest quartile. PROSE-ICD includes patients greater than 18 years
        old who have a history of acute MI at least 4 weeks old (confirmed by persistent pathologic
        Q waves on ECG, CPK-MB > three times the upper limit of normal, or a fixed perfusion defect
        on nuclear imaging) or non-ischemic LV dysfunction for at least 9 months who have an EF ≤
        35% and who have undergone implantation of an FDA-approved ICD for primary prevention of
        SCD within 2 weeks of enrollment.

        Exclusion Criteria Exclusion criteria for PROSE-ICD include an indication for ICD
        implantation for secondary prevention; inability or unwillingness to provide informed
        consent; women <50 years old with anatomic child-bearing potential who are unwilling to use
        contraceptives; NYHA class IV HF; patients with permanent pacemakers; and unsuccessful ICD

        Additional exclusion criteria for PROSE-ICD patients enrolled in MIBG imaging will include:

          1. Positive pregnancy test in women with child bearing potential

          2. Use of a medication for non-cardiac conditions that may interfere with MIBG that
             cannot be safely withheld for five half-lives before study procedures.

          3. Renal insufficiency (GFR <30 ml/dl or creatinine >3.0 mg/dl) or dialysis.

          4. Hypersensitivity to iodine.




18 Years - N/A

Accepts Healthy Volunteers



Richard T George, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Secondary IDs


Responsible Party


Study Sponsor

Johns Hopkins University


 National Institutes of Health (NIH)

Study Sponsor

Richard T George, M.D., Principal Investigator, Johns Hopkins University

Verification Date

December 2017