Myocardial ATP depletion detected noninvasively predicts sudden cardiac death risk in patients with heart failure
T. Jake Samuel, Shenghan Lai, Michael Schär, Katherine C. Wu, Angela M. Steinberg, An-Chi Wei, Mark E. Anderson, Gordon F. Tomaselli, Gary Gerstenblith, Paul A. Bottomley, Robert G. Weiss
T. Jake Samuel, Shenghan Lai, Michael Schär, Katherine C. Wu, Angela M. Steinberg, An-Chi Wei, Mark E. Anderson, Gordon F. Tomaselli, Gary Gerstenblith, Paul A. Bottomley, Robert G. Weiss
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Clinical Research and Public Health Cardiology

Myocardial ATP depletion detected noninvasively predicts sudden cardiac death risk in patients with heart failure

Abstract

BACKGROUND Sudden cardiac death (SCD) remains a worldwide public health problem in need of better noninvasive predictive tools. Current guidelines for primary preventive SCD therapies, such as implantable cardioverter defibrillators (ICDs), are based on left ventricular ejection fraction (LVEF), but these guidelines are imprecise: fewer than 5% of ICDs deliver lifesaving therapy per year. Impaired cardiac metabolism and ATP depletion cause arrhythmias in experimental models, but to our knowledge a link between arrhythmias and cardiac energetic abnormalities in people has not been explored, nor has the potential for metabolically predicting clinical SCD risk.METHODS We prospectively measured myocardial energy metabolism noninvasively with phosphorus magnetic resonance spectroscopy in patients with no history of significant arrhythmias prior to scheduled ICD implantation for primary prevention in the setting of reduced LVEF (≤35%).RESULTS By 2 different analyses, low myocardial ATP significantly predicted the composite of subsequent appropriate ICD firings for life-threatening arrhythmias and cardiac death over approximately 10 years. Life-threatening arrhythmia risk was approximately 3-fold higher in patients with low ATP and independent of established risk factors, including LVEF. In patients with normal ATP, rates of appropriate ICD firings were several-fold lower than reported rates of ICD complications and inappropriate firings.CONCLUSION To the best of our knowledge, these are the first data linking in vivo myocardial ATP depletion and subsequent significant arrhythmic events in people, suggesting an energetic component to clinical life-threatening ventricular arrhythmogenesis. The findings support investigation of metabolic strategies that limit ATP loss to treat or prevent life-threatening cardiac arrhythmias and herald noninvasive metabolic imaging as a complementary SCD risk stratification tool.TRIAL REGISTRATION ClinicalTrials.gov NCT00181233.FUNDING This work was supported by the DW Reynolds Foundation, the NIH (grants HL61912, HL056882, HL103812, HL132181, HL140034), and Russell H. Morgan and Clarence Doodeman endowments at Johns Hopkins.

Authors

T. Jake Samuel, Shenghan Lai, Michael Schär, Katherine C. Wu, Angela M. Steinberg, An-Chi Wei, Mark E. Anderson, Gordon F. Tomaselli, Gary Gerstenblith, Paul A. Bottomley, Robert G. Weiss

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Figure 2

Event-free survival in patients with low versus normal myocardial energetics.

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Event-free survival in patients with low versus normal myocardial energe...
Kaplan-Meier curves depicting the proportion of event-free survival across a median follow-up period of 10.7 years (range: 3.2–14.7 years) in individuals with low (solid line) versus individuals with normal (dashed line) myocardial high-energy phosphates. We defined low myocardial energetics as 2 standard deviations below the grouped mean of healthy individuals previously reported by our group (ATP: <3.4 μmol/g; PCr: <7.6 μmol/g; CK flux: <1.3 μmol/g/s) (7, 9). Cardiac PCr/ATP cut point was less than 1.6, as previously reported (8). (A, C, E, and G) Event-free survival is shown where the event was defined as the composite endpoint of appropriate ICD firing or cardiac death. (B, D, F, and H) Event-free survival is shown where the event was defined as appropriate ICD firing only. Low myocardial ATP concentration was associated with lower event-free survival when considering the composite endpoint (log-rank, P = 0.0079) or appropriate ICD firing alone (log-rank, P = 0.024). Neither low PCr or low CK flux were significant predictors of event-free survival (log rank, P > 0.05). (A and B) n = 32 versus 14 (normal versus low ATP); (C and D) n = 17 versus 29 (normal versus low PCr); (E and F) n = 28 versus 13 (normal versus low CK flux); (G and H) n = 30 versus 16 (normal versus low PCr/ATP).