Inflammation, Cardiac Sympathetic Innervation, and Arrhythmic Sudden Death
| Status: | Completed |
|---|---|
| Conditions: | Cardiology, Cardiology, Cardiology |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 12/10/2017 |
| Start Date: | March 2012 |
| End Date: | September 2014 |
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, 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).
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, 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).
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
imaging.
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
study.
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.
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
imaging.
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
study.
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.
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
implantation
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.
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