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

ABSTRACT: BACKGROUNDSudden 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.METHODSWe 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%).RESULTSBy 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.CONCLUSIONTo 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 REGISTRATIONClinicalTrials.gov NCT00181233.FUNDINGThis 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.

SUBMITTER: Samuel TJ

PROVIDER: S-EPMC9309047 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Sudden cardiac death (SCD) associated with heart failure (HF) is a multifactorial problem requiring a systems level approach applied to suitable experimental animal models with features of the human disease. Here we examine key regulatory pathways underlying the transition from compensated hypertrophy (HYP) to decompensated HF and SCD by integrated analysis of the transcriptome, proteome and metabolome. In a guinea pig model of acquired long QT syndrome and HF/SCD, relative protein abundances from sham-operated, HYP and HF hearts were assessed using isobaric tags for relative and absolute quantification (iTRAQ), prior to liquid chromatography and tandem mass spectrometry (LC-MS/MS). Metabolites were quantified by LC-MS/MS or gas chromatography coupled to MS (GC-MS). Transcriptome profiles were obtained using DNA microarrays. The guinea pig HF proteome exhibited classic biosignatures of cardiac HYP, left ventricular dysfunction, fibrosis, cellular degeneration, inflammation and extravasation. Fatty acid metabolism, mitochondrial transcription/translation factors, antioxidant enzymes, and other mitochondrial processes, were downregulated in HF, but not HYP. Proteins upregulated in HF are consistent with extracellular matrix remodeling, cytoskeletal remodeling, and acute phase inflammation markers. Among metabolites, downregulation of acyl-carnitines was observed in HYP, while fatty acids accumulated in HF. Levels of the tricarboxylic acid (TCA) cycle metabolite, citrate, and the potent inhibitor, 2-methylcitrate, increased upon transition from HYP to HF. Correlation of the magnitude of transcript and protein changes in HF is weak (R2=0.23), indicating that targeting transcript/proteome may reveal inform post-transcriptional gene regulation in HF. Proteome/Metabolome integration suggests metabolic bottlenecks in fatty acyl-CoA processing by carnitine palmitoyl transferase (CPT1B) as well as TCA cycle inhibition. We present a model in which hallmarks of acute signaling in HF, including Ca2+ dysregulation and low cAMP levels, are coupled to mitochondrial metabolic and antioxidant defects, through a CREB/PGC1-alpha transcriptional axis.

Project description:BackgroundThe incidence of sudden cardiac death and sudden death caused by arrhythmia, as determined by autopsy, in persons with human immunodeficiency virus (HIV) infection has not been clearly established.MethodsBetween February 1, 2011, and September 16, 2016, we prospectively identified all new deaths due to out-of-hospital cardiac arrest among persons 18 to 90 years of age, with or without known HIV infection, for comprehensive autopsy and toxicologic and histologic testing. We compared the rates of sudden cardiac death and sudden death caused by arrhythmia between groups.ResultsOf 109 deaths from out-of-hospital cardiac arrest among 610 unexpected deaths in HIV-positive persons, 48 met World Health Organization criteria for presumed sudden cardiac death; of those, fewer than half (22) had an arrhythmic cause. A total of 505 presumed sudden cardiac deaths occurred between February 1, 2011, and March 1, 2014, in persons without known HIV infection. Observed incidence rates of presumed sudden cardiac death were 53.3 deaths per 100,000 person-years among persons with known HIV infection and 23.7 deaths per 100,000 person-years among persons without known HIV infection (incidence rate ratio, 2.25; 95% confidence interval [CI], 1.37 to 3.70). Observed incidence rates of sudden death caused by arrhythmia were 25.0 and 13.3 deaths per 100,000 person-years, respectively (incidence rate ratio, 1.87; 95% CI, 0.93 to 3.78). Among all presumed sudden cardiac deaths, death due to occult drug overdose was more common in persons with known HIV infection than in persons without known HIV infection (34% vs. 13%). Persons who were HIV-positive had higher histologic levels of interstitial myocardial fibrosis than persons without known HIV infection.ConclusionsIn this postmortem study, the rates of presumed sudden cardiac death and myocardial fibrosis were higher among HIV-positive persons than among those without known HIV infection. One third of apparent sudden cardiac deaths in HIV-positive persons were due to occult drug overdose. (Supported by the National Heart, Lung, and Blood Institute.).

Project description:OBJECTIVES:The PAREPET (Prediction of ARrhythmic Events with Positron Emission Tomography) study sought to test the hypothesis that quantifying inhomogeneity in myocardial sympathetic innervation could identify patients at highest risk for sudden cardiac arrest (SCA). BACKGROUND:Left ventricular ejection fraction (LVEF) is the only parameter identifying patients at risk of SCA who benefit from an implantable cardiac defibrillator (ICD). METHODS:We prospectively enrolled 204 subjects with ischemic cardiomyopathy (LVEF ?35%) eligible for primary prevention ICDs. Positron emission tomography (PET) was used to quantify myocardial sympathetic denervation ((11)C-meta-hydroxyephedrine [(11)C-HED]), perfusion ((13)N-ammonia) and viability (insulin-stimulated (18)F-2-deoxyglucose). The primary endpoint was SCA defined as arrhythmic death or ICD discharge for ventricular fibrillation or ventricular tachycardia >240 beats/min. RESULTS:After 4.1 years follow-up, cause-specific SCA was 16.2%. Infarct volume (22 ± 7% vs. 19 ± 9% of left ventricle [LV]) and LVEF (24 ± 8% vs. 28 ± 9%) were not predictors of SCA. In contrast, patients developing SCA had greater amounts of sympathetic denervation (33 ± 10% vs. 26 ± 11% of LV; p = 0.001) reflecting viable, denervated myocardium. The lower tertiles of sympathetic denervation had SCA rates of 1.2%/year and 2.2%/year, whereas the highest tertile had a rate of 6.7%/year. Multivariate predictors of SCA were PET sympathetic denervation, left ventricular end-diastolic volume index, creatinine, and no angiotensin inhibition. With optimized cut-points, the absence of all 4 risk factors identified low risk (44% of cohort; SCA <1%/year); whereas ?2 factors identified high risk (20% of cohort; SCA ?12%/year). CONCLUSIONS:In ischemic cardiomyopathy, sympathetic denervation assessed using (11)C-HED PET predicts cause-specific mortality from SCA independently of LVEF and infarct volume. This may provide an improved approach for the identification of patients most likely to benefit from an ICD. (Prediction of ARrhythmic Events With Positron Emission Tomography [PAREPET]; NCT01400334).

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

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