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Mitochondrial ROS Drive Sudden Cardiac Death and Chronic Proteome Remodeling in Heart Failure.

ABSTRACT: RATIONALE:Despite increasing prevalence and incidence of heart failure (HF), therapeutic options remain limited. In early stages of HF, sudden cardiac death (SCD) from ventricular arrhythmias claims many lives. Reactive oxygen species (ROS) have been implicated in both arrhythmias and contractile dysfunction. However, little is known about how ROS in specific subcellular compartments contribute to HF or SCD pathophysiology. The role of ROS in chronic proteome remodeling has not been explored. OBJECTIVE:We will test the hypothesis that elevated mitochondrial ROS (mROS) is a principal source of oxidative stress in HF and in vivo reduction of mROS mitigates SCD. METHODS AND RESULTS:Using a unique guinea pig model of nonischemic HF that recapitulates important features of human HF, including prolonged QT interval and high incidence of spontaneous arrhythmic SCD, compartment-specific ROS sensors revealed increased mROS in resting and contracting left ventricular myocytes in failing hearts. Importantly, the mitochondrially targeted antioxidant (MitoTEMPO) normalized global cellular ROS. Further, in vivo MitoTEMPO treatment of HF animals prevented and reversed HF, eliminated SCD by decreasing dispersion of repolarization and ventricular arrhythmias, suppressed chronic HF-induced remodeling of the expression proteome, and prevented specific phosphoproteome alterations. Pathway analysis of mROS-sensitive networks indicated that increased mROS in HF disrupts the normal coupling between cytosolic signals and nuclear gene programs driving mitochondrial function, antioxidant enzymes, Ca2+ handling, and action potential repolarization, suggesting new targets for therapeutic intervention. CONCLUSIONS:mROS drive both acute emergent events, such as electrical instability responsible for SCD, and those that mediate chronic HF remodeling, characterized by suppression or altered phosphorylation of metabolic, antioxidant, and ion transport protein networks. In vivo reduction of mROS prevents and reverses electrical instability, SCD, and HF. Our findings support the feasibility of targeting the mitochondria as a potential new therapy for HF and SCD while identifying new mROS-sensitive protein modifications.

SUBMITTER: Dey S

PROVIDER: S-EPMC6057154 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Mitochondrial ROS Drive Sudden Cardiac Death and Chronic Proteome Remodeling in Heart Failure.

Dey Swati S DeMazumder Deeptankar D Sidor Agnieszka A Foster D Brian DB O'Rourke Brian B

Circulation research 20180613 3

<h4>Rationale</h4>Despite increasing prevalence and incidence of heart failure (HF), therapeutic options remain limited. In early stages of HF, sudden cardiac death (SCD) from ventricular arrhythmias claims many lives. Reactive oxygen species (ROS) have been implicated in both arrhythmias and contractile dysfunction. However, little is known about how ROS in specific subcellular compartments contribute to HF or SCD pathophysiology. The role of ROS in chronic proteome remodeling has not been expl ...[more]

PMID: 29898892

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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:Here we examine key regulatory pathways underlying the transition from compensated hypertrophy (HYP) to decompensated heart failure (HF) and sudden cardiac death (SCD) in a guinea pig model by integrated multi-ome analysis. Relative protein abundances from sham-operated, HYP and HF hearts were assessed by iTRAQ shotgun LC-MS/MS. Metabolites were quantified by LC-MS/MS or GC-MS. Transcriptome profiles were obtained using DNA microarrays. The guinea pig HF proteome exhibited classic biosignatures of cardiac HYP, left ventricular dysfunction, fibrosis, 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 implicate 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. Correlation of transcript and protein changes in HF is weak (R2=0.23), suggesting transcript/proteome divergence may reveal 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 by which acute signaling in HF, including Ca2+ dysregulation and low cAMP levels, is coupled to mitochondrial metabolic and antioxidant defects, through a CREB/PGC1 transcriptional axis. Animal Model The guinea pig model of heart failure and sudden cardiac death has been described previously. Briefly, the HF and SCD guinea pig model was produced by combining ascending aortic constriction (AC) and daily isoproterenol challenge (ACi model). Specifically, Hartley guinea pigs (~250 g; Hilltop Lab Animals) were anesthetized with 4% isoflurane in a closed box for 4min, and then intubated and ventilated with oxygen and 2% isoflurane. Ascending aortic constriction (AC) was produced by tying a suture around the ascending aorta using an 18‐gauge needle as a spacer, which was then removed. For sham operations the procedure was identical though the suture was not tied. After the procedure, bupronex (0.05 mg/kg) was administered via intramuscular injection for analgesia and animals were observed until full recovery. Isoproterenol was administered daily by intra peritoneal injection at 1 mg/kg for the first week after surgery and at 2 mg/kg for a subsequent 3 weeks. As characterized previously (1), cardiac function of ACi animal is well compensated in the first 2 weeks (HYP) but declined rapidly thereafter (HF). Hypertrophic heart was collected between 1-2 weeks post-surgery (ACi-2w), whereas failing heart was collected at 4 weeks after surgery (ACi-4w). Following retrograde perfusion with 20ml Tyrode’s solution, excised hearts were Snap-frozen in liquid N2 and stored at -80°C Experimental Design The experiment consisted of 3 treatment groups: 1) HYP (ACi-2wk), 2) HF (ACi-4wk) 3) sham-operated animals with daily administration for 4 weeks (Shami-4w). 1 heart from each group was included in an iTRAQ 4-plex experiment wherein peptides from each heart are subjected to reaction with an isobaric label. The experiment was repeated twice, yielding a total of 3 independent experiments quantifying the peptides from 9 hearts. ITRAQ reagents were shuffled among treatment groups for each experiment to minimize labeling bias.

Project description: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.

Project description:AimsHeart failure (HF) patients have a high risk of mortality due to sudden cardiac death (SCD) and non-SCD, including pump failure death (PFD). Anaemia predicts more severe symptomatic burden and higher morbidity, as noted by markedly increased hospitalizations and readmission rates, and mortality, underscoring its importance in HF management. Herein, we aimed to determine whether haemoglobin (Hb) level at discharge affects the mode of death and influences SCD risk prediction.MethodsWe evaluated the data of 3020 consecutive acute HF patients from a Japanese prospective multicentre registry. Patients were divided into four groups based on discharge Hb levels. SCD was defined as an unexpected and otherwise unexplained death in a previously stable patient or death due to documented or presumed cardiac arrhythmia without a clear non-cardiovascular cause. The mode of death (SCD, PFD or other cause) was adjudicated by a central committee. Finally, we investigated whether adding Hb level to the Seattle Proportional Risk Model (SPRM; established risk score utilized to estimate 'proportion' of SCD among death events) would affect its performance.ResultsThe mean age of studied patients was 74.3 ± 12.9 years, and 59.8% were male. The mean Hb level was 12.0 ± 2.1 g/dL (61.3% of patients had anaemia defined by World Health Organization criteria). During the 2-year follow-up, 474 deaths (15.7%) occurred, including 93 SCDs (3.1%), 171 PFDs (5.7%) and 210 other deaths (7.0%; predominantly non-cardiac death). Absolute risk of PFD (P < 0.001) or other death (P < 0.001) increased along with the severity of anaemia, whereas the incidence of SCD was low but remained consistent across all four groups (P = 0.440). As a proportion of total deaths in each Hb level group, the contributions from non-SCD increased and from SCD decreased along with anaemia severity (P = 0.007). Adding Hb level to the SPRM improved the overall discrimination (c-index: 0.62 [95% confidence interval (CI) 0.56-0.69] to 0.65 [95% CI 0.59-0.71]), regardless of the baseline ejection fraction (EF) (c-index: 0.64 [95% CI 0.55-0.73] to 0.67 [95% CI 0.58-0.75] for reduced EF and 0.55 [95% CI 0.45-0.66] to 0.61 [95% CI 0.52-0.70] for preserved EF).ConclusionsThe discharge Hb level provides information about both absolute and proportional risks for each mode of death in acute HF patients, and the addition of Hb level improves the performance of SPRM by identifying more non-SCD cases. Future 'proportional' SCD risk models should incorporate Hb level as a covariate to meet this high performance.

Dataset Information

Mitochondrial ROS Drive Sudden Cardiac Death and Chronic Proteome Remodeling in Heart Failure.

Publications

Mitochondrial ROS Drive Sudden Cardiac Death and Chronic Proteome Remodeling in Heart Failure.

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