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Canadian Journal of Cardiology

N-Terminal Pro B-Type Natriuretic Peptide and High-Sensitivity Cardiac Troponin T Levels Are Related to the Extent of Hibernating Myocardium in Patients With Ischemic Heart Failure

  • Jason G.E. Zelt
    Affiliations
    Molecular Function and Imaging Program, The National Cardiac PET Centre, and the Advanced Heart Disease Program, Division of Cardiology, Department of Medicine, and the Cardiac Research Methods Centre, University of Ottawa Heart Institute and University of Ottawa, Ottawa, Ontario, Canada

    Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
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  • Peter P. Liu
    Affiliations
    Molecular Function and Imaging Program, The National Cardiac PET Centre, and the Advanced Heart Disease Program, Division of Cardiology, Department of Medicine, and the Cardiac Research Methods Centre, University of Ottawa Heart Institute and University of Ottawa, Ottawa, Ontario, Canada

    Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada

    Departments of Medicine and Physiology, University of Toronto, Toronto, Ontario, Canada
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  • Fernanda Erthal
    Affiliations
    Molecular Function and Imaging Program, The National Cardiac PET Centre, and the Advanced Heart Disease Program, Division of Cardiology, Department of Medicine, and the Cardiac Research Methods Centre, University of Ottawa Heart Institute and University of Ottawa, Ottawa, Ontario, Canada
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  • Robert A. deKemp
    Affiliations
    Molecular Function and Imaging Program, The National Cardiac PET Centre, and the Advanced Heart Disease Program, Division of Cardiology, Department of Medicine, and the Cardiac Research Methods Centre, University of Ottawa Heart Institute and University of Ottawa, Ottawa, Ontario, Canada
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  • George Wells
    Affiliations
    Molecular Function and Imaging Program, The National Cardiac PET Centre, and the Advanced Heart Disease Program, Division of Cardiology, Department of Medicine, and the Cardiac Research Methods Centre, University of Ottawa Heart Institute and University of Ottawa, Ottawa, Ontario, Canada
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  • Eileen O'Meara
    Affiliations
    Division of Cardiology, Montréal Heart Institute, Montréal, Québec, Canada
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  • Linda Garrard
    Affiliations
    Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
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  • Author Footnotes
    ∗ These authors contributed equally to this work.
    Rob S.B. Beanlands
    Footnotes
    ∗ These authors contributed equally to this work.
    Affiliations
    Molecular Function and Imaging Program, The National Cardiac PET Centre, and the Advanced Heart Disease Program, Division of Cardiology, Department of Medicine, and the Cardiac Research Methods Centre, University of Ottawa Heart Institute and University of Ottawa, Ottawa, Ontario, Canada

    Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
    Search for articles by this author
  • Author Footnotes
    ∗ These authors contributed equally to this work.
    Lisa M. Mielniczuk
    Correspondence
    Corresponding author: Dr Lisa M. Mielniczuk, 40 Ruskin St, Ottawa, Ontario K1Y 4W7, Canada. Tel.: +1-613-761-4059; fax: +1-613-761-4877.
    Footnotes
    ∗ These authors contributed equally to this work.
    Affiliations
    Molecular Function and Imaging Program, The National Cardiac PET Centre, and the Advanced Heart Disease Program, Division of Cardiology, Department of Medicine, and the Cardiac Research Methods Centre, University of Ottawa Heart Institute and University of Ottawa, Ottawa, Ontario, Canada

    Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
    Search for articles by this author
  • Author Footnotes
    ∗ These authors contributed equally to this work.

      Abstract

      Background

      Increased N-terminal pro b-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) can identify patients with heart failure (HF) who are at increased risk of cardiac events. The relationship of these biomarkers to the extent of hibernating myocardium and scar has not been previously characterized in patients with ischemic left ventricular dysfunction and HF.

      Methods

      Patients with ischemic HF meeting recruitment criteria and undergoing perfusion and fluorodeoxyglucose–positron emission tomography to define myocardial hibernation and scar were included in the study. A total of 39 patients (mean age 67 ± 8 years) with New York Heart Association class II-IV HF and ischemic cardiomyopathy (ejection fraction [EF], 27.9% ± 8.5%) were enrolled in the study.

      Results

      Serum NT-proBNP and hs-cTnT levels were elevated in patients with ≥ 10% hibernating myocardium compared with those with < 10% (NT-pro-BNP, 7419.10 ± 7169.5 pg/mL vs 2894.6 ± 2967.4 pg/mL; hs-cTnT, 789.3 ± 1835.3 pg/mL vs 44.8 ± 78.9 pg/mL; P < 0.05). The overall receiver operating characteristic under the curve value for NT-proBNP and hs-cTnT to predict hibernating myocardium was 0.76 and 0.78, respectively (P < 0.05). The NT-proBNP (P = 0.02) and hs-cTnT (P < 0.0001) levels also correlated with hibernation, particularly in patients with ≥ 10% scar, independent of EF, age, and estimated glomerular filtration rate. No differences were noted in biomarker levels for patients with vs those without ≥ 10% scar.

      Conclusions

      NT-proBNP and hs-cTnT levels are elevated in patients with ischemic HF hibernation and are correlated with the degree of hibernation but not with the presence or extent of scar. Taken together, these data support the novel concept that NT-proBNP and hs-cTnT release in patients with ischemic HF reflects the presence and extent of hibernating myocardium.

      Résumé

      Introduction

      L’augmentation du propeptide natriurétique de type B N-terminale (NT-proBNP) et de la troponine T cardiaque à haute sensibilité (TnTc-hs) permet de repérer les patients atteints d’insuffisance cardiaque (IC) qui sont exposés à un risque accru d’événements cardiaques. La relation de ces biomarqueurs avec l’ampleur de l’hibernation et des cicatrices myocardiques n’a pas encore été définie chez les patients atteints d’une dysfonction ventriculaire gauche et d’une IC d’origine ischémique.

      Méthodes

      Les patients atteints d’une IC d’origine ischémique qui répondaient aux critères de recrutement et qui subissaient une perfusion et une tomographie par émission de positons au fluorodésoxyglucose pour définir l’hibernation et les cicatrices myocardiques ont été inclus dans l’étude. Un total de 39 patients (âge moyen de 67 ± 8 ans) atteints d’une IC et d’une cardiomyopathie d’origine ischémique de classe II à IV de la New York Heart Association (fraction d’éjection [FE], 27,9 % ± 8,5 %) ont été inscrits à l’étude.

      Résultats

      Les concentrations sériques de NT-proBNP et de TnTc-hs étaient élevées chez les patients qui présentaient une hibernation myocardique ≥ 10 % comparativement à ceux qui présentaient une hibernation myocardique < 10 % (NT-proBNP, 7419,10 ± 7169,5 pg/ml vs 2894,6 ± 2967,4 pg/ml ; TnTc-hs, 789,3 ± 1835,3 pg/ml vs 44,8 ± 78,9 pg/ml ; P < 0,05). La valeur globale de l’aire sous la courbe ROC (Receiver Operating Characteristic) du NT-proBNP et de la TnTc-hs pour prédire l’hibernation myocardique était respectivement de 0,76 et de 0,78 (P < 0,05). Les concentrations de NT-proBNP (P = 0,02) et de TnTc-hs (P < 0,0001) corrélaient aussi avec l’hibernation, particulièrement chez les patients ayant des cicatrices ≥ 10 %, indépendamment de la FE, de l’âge et de l’estimation des débits de filtration glomérulaire. On ne notait aucune différence dans les concentrations des biomarqueurs chez les patients ayant des cicatrices ≥ 10 % par rapport à ceux n’ayant pas de cicatrices ≥ 10 %.

      Conclusions

      Les concentrations de NT-proBNP et de TnTc-hs étaient élevées chez les patients ayant une hibernation d’IC d’origine ischémique et corrélaient au degré d’hibernation, mais non avec la présence ou l’ampleur des cicatrices. Ensemble, ces données appuient le nouveau concept selon lequel la libération de NT-proBNP et de TnTc-hs chez les patients atteints d’IC d’origine ischémique reflète la présence et l’ampleur de l’hibernation myocardique.
      Coronary artery disease (CAD) is the leading cause of heart failure (HF).
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      Increasing benefit from revascularization is associated with increasing amounts of myocardial hibernation: a substudy of the PARR-2 trial.
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      Positron emission tomography and recovery following revascularization (PARR-1): the importance of scar and the development of a prediction rule for the degree of recovery of left ventricular function.
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      Long-term follow-up of outcomes with F-18-fluorodeoxyglucose positron emission tomography imaging-assisted management of patients with severe left ventricular dysfunction secondary to coronary disease.
      Cardiac imaging modalities have emerged with the ability to differentiate between myocardial scar and viable myocardium and are now often used to direct therapeutic decisions, including revascularization,
      • Rouleau J.L.
      • Bonow R.O.
      An approach to the rational use of revascularization in heart failure patients.
      • Mielniczuk L.M.
      • Beanlands R.S.
      Does imaging-guided selection of patients with ischemic heart failure for high risk revascularization improve identification of those with the highest clinical benefit? Imaging-guided selection of patients with ischemic heart failure for high-risk revascularization improves identification of those with the highest clinical benefit.
      • Abraham A.
      • Nichol G.
      • Williams K.A.
      • et al.
      18F-FDG-PET imaging of myocardial viability in an experienced center with access to 18F-FDG and integration with clinical management teams: the Ottawa-FIVE substudy of the PARR 2 trial.
      • Schinkel A.F.L.
      • Bax J.J.
      • Poldermans D.
      • et al.
      Hibernating myocardium: diagnosis and patient outcomes.
      • Ling L.F.
      • Marwick T.H.
      • Flores D.R.
      • et al.
      Identification of therapeutic benefit from revascularization in patients with left ventricular systolic dysfunction: inducible ischemia versus hibernating myocardium.
      • Beanlands R.S.B.
      • Nichol G.
      • Huszti E.
      • et al.
      F-18-fluorodeoxyglucose positron emission tomography imaging-assisted management of patients with severe left ventricular dysfunction and suspected coronary disease: a randomized, controlled trial (PARR-2).
      • D'Egidio G.
      • Nichol G.
      • Williams K.A.
      • et al.
      Increasing benefit from revascularization is associated with increasing amounts of myocardial hibernation: a substudy of the PARR-2 trial.
      • Beanlands R.S.B.
      • Ruddy T.D.
      • deKemp R.A.
      • et al.
      Positron emission tomography and recovery following revascularization (PARR-1): the importance of scar and the development of a prediction rule for the degree of recovery of left ventricular function.
      • McArdle B.
      • Shukla T.
      • Nichol G.
      • et al.
      Long-term follow-up of outcomes with F-18-fluorodeoxyglucose positron emission tomography imaging-assisted management of patients with severe left ventricular dysfunction secondary to coronary disease.
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      • et al.
      Impact of ischaemia and scar on the therapeutic benefit derived from myocardial revascularization vs. medical therapy among patients undergoing stress-rest myocardial perfusion scintigraphy.
      • Gerber B.L.
      • Rousseau M.F.
      • Ahn S.A.
      • et al.
      Prognostic value of myocardial viability by delayed-enhanced magnetic resonance in patients with coronary artery disease and low ejection fraction: impact of revascularization therapy.
      • Pagano D.
      • Bonser R.S.
      • Townend J.N.
      • et al.
      Predictive value of dobutamine echocardiography and positron emission tomography in identifying hibernating myocardium in patients with postischaemic heart failure.
      • Di Carli M.F.
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      • Little R.
      • et al.
      Value of metabolic imaging with positron emission tomography for evaluating prognosis in patients with coronary artery disease and left ventricular dysfunction.
      • Allman K.C.
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      • Hachamovitch R.
      • Udelson J.E.
      Myocardial viability testing and impact of revascularization on prognosis in patients with coronary artery disease and left ventricular dysfunction: a meta-analysis.
      Among these, cardiac positron emission tomography (PET) using fluorodeoxyglucose (FDG) is widely considered to be the gold standard and the most sensitive modality for detecting hibernating viable myocardium.
      • Mielniczuk L.M.
      • Beanlands R.S.
      Does imaging-guided selection of patients with ischemic heart failure for high risk revascularization improve identification of those with the highest clinical benefit? Imaging-guided selection of patients with ischemic heart failure for high-risk revascularization improves identification of those with the highest clinical benefit.
      • Schinkel A.F.L.
      • Bax J.J.
      • Poldermans D.
      • et al.
      Hibernating myocardium: diagnosis and patient outcomes.
      • Pagano D.
      • Bonser R.S.
      • Townend J.N.
      • et al.
      Predictive value of dobutamine echocardiography and positron emission tomography in identifying hibernating myocardium in patients with postischaemic heart failure.
      However, the evidence is conflicting as to whether viability imaging-guided strategies alone can yield significant clinical benefit on revascularization. Some studies do suggest benefits,
      • Abraham A.
      • Nichol G.
      • Williams K.A.
      • et al.
      18F-FDG-PET imaging of myocardial viability in an experienced center with access to 18F-FDG and integration with clinical management teams: the Ottawa-FIVE substudy of the PARR 2 trial.
      • Schinkel A.F.L.
      • Bax J.J.
      • Poldermans D.
      • et al.
      Hibernating myocardium: diagnosis and patient outcomes.
      • Ling L.F.
      • Marwick T.H.
      • Flores D.R.
      • et al.
      Identification of therapeutic benefit from revascularization in patients with left ventricular systolic dysfunction: inducible ischemia versus hibernating myocardium.
      • Beanlands R.S.B.
      • Nichol G.
      • Huszti E.
      • et al.
      F-18-fluorodeoxyglucose positron emission tomography imaging-assisted management of patients with severe left ventricular dysfunction and suspected coronary disease: a randomized, controlled trial (PARR-2).
      • D'Egidio G.
      • Nichol G.
      • Williams K.A.
      • et al.
      Increasing benefit from revascularization is associated with increasing amounts of myocardial hibernation: a substudy of the PARR-2 trial.
      • Beanlands R.S.B.
      • Ruddy T.D.
      • deKemp R.A.
      • et al.
      Positron emission tomography and recovery following revascularization (PARR-1): the importance of scar and the development of a prediction rule for the degree of recovery of left ventricular function.
      • McArdle B.
      • Shukla T.
      • Nichol G.
      • et al.
      Long-term follow-up of outcomes with F-18-fluorodeoxyglucose positron emission tomography imaging-assisted management of patients with severe left ventricular dysfunction secondary to coronary disease.
      • Gerber B.L.
      • Rousseau M.F.
      • Ahn S.A.
      • et al.
      Prognostic value of myocardial viability by delayed-enhanced magnetic resonance in patients with coronary artery disease and low ejection fraction: impact of revascularization therapy.
      • Pagano D.
      • Bonser R.S.
      • Townend J.N.
      • et al.
      Predictive value of dobutamine echocardiography and positron emission tomography in identifying hibernating myocardium in patients with postischaemic heart failure.
      • Di Carli M.F.
      • Davidson M.
      • Little R.
      • et al.
      Value of metabolic imaging with positron emission tomography for evaluating prognosis in patients with coronary artery disease and left ventricular dysfunction.
      • Allman K.C.
      • Shaw L.J.
      • Hachamovitch R.
      • Udelson J.E.
      Myocardial viability testing and impact of revascularization on prognosis in patients with coronary artery disease and left ventricular dysfunction: a meta-analysis.
      whereas others suggest no significant role.
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      • et al.
      Myocardial viability and survival in ischemic left ventricular dysfunction.
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      • Asch F.M.
      • et al.
      Inducible myocardial ischemia and outcomes in patients with coronary artery disease and left ventricular dysfunction.
      Hence, there remains a need to improve approaches to better identify patients with ischemic HF who are likely to benefit from revascularization.
      Cardiac-specific biomarkers, such as brain natriuretic peptide (BNP) and cardiac troponin T (cTnT) are excellent prognosticators in patients with HF.
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      Writing Committee Members
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      Novel heart failure biomarkers predict improvement of mitral regurgitation in patients receiving cardiac resynchronization therapy—the BIOCRT Study.
      They may offer an additional approach to compliment current image-guided strategies for patient selection. However, it is largely unknown how cardiac-specific biomarkers are released in relation to the presence and extent of myocardial scar and hibernation in patients with ischemic HF. This relationship may provide additional insights about the underlying pathophysiological characteristics of biomarker dynamics in ischemic HF.
      The objectives of this study were to assess the relationship and interaction of the biomarkers N-terminal pro b-type natriuretic peptide (NT-proBNP) and high-sensitivity cTnT (hs-cTnT) with myocardial scar and hibernation in patients with chronic ischemic HF.

      Methods

      Patients with suspected ischemic cardiomyopathy were prospectively recruited into an imaging study using cardiac PET to determine perfusion deficit, scar, or hibernation. The patients also had blood sampling at baseline to determine biomarkers.
      The patients were part of the overall Imaging Modalities to Assist With Guiding Therapy in The Evaluation of Patients with Heart Failure (IMAGE HF) program and its subproject Alternative Imaging Modalities in Ischemic Heart Failure (AIMI-HF) (www.ClincalTrials.gov: NCT01288560).
      • O'Meara E.
      • Mielniczuk L.M.
      • Wells G.A.
      • et al.
      Alternative Imaging Modalities in Ischemic Heart Failure (AIMI-HF) IMAGE HF Project I-A: study protocol for a randomized controlled trial.
      Full details on the AIMI-HF study design and methods have been published separately.
      • O'Meara E.
      • Mielniczuk L.M.
      • Wells G.A.
      • et al.
      Alternative Imaging Modalities in Ischemic Heart Failure (AIMI-HF) IMAGE HF Project I-A: study protocol for a randomized controlled trial.
      This study was approved by the University of Ottawa Heart Institute (UOHI) Human Research Ethics Board (protocol No. 2010620-01H). It was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice and TriCouncil Policy guidelines.

      Patients

      Patients in this study met the AIMI-HF enrollment criteria.
      • O'Meara E.
      • Mielniczuk L.M.
      • Wells G.A.
      • et al.
      Alternative Imaging Modalities in Ischemic Heart Failure (AIMI-HF) IMAGE HF Project I-A: study protocol for a randomized controlled trial.
      Briefly, patients with clinical HF or severe LV systolic dysfunction who needed further definition of viability or scar were enrolled. Eligible patients were included if they were 18 years of age or older, had known or highly suspected CAD documented by coronary angiography or by a history of previous myocardial infarction (MI), or evidence of moderate ischemia or scar based on previous imaging. Patients were being treated with optimal medical therapy, and their LV dysfunction was primarily attributable to ischemic heart disease with (1) an ejection fraction (EF) ≤ 45% as documented by echocardiography, radionuclide angiography, LV angiography, PET, or single-photon emission computed tomography (SPECT) or by cardiac magnetic resonance imaging (MRI) in the previous 6 months and New York Heart Association (NYHA) class II to IV symptoms or (2) an EF ≤ 30% within the previous 6 months and NYHA class I-IV symptoms. Patients receiving renal replacement therapy were excluded from this biomarker study.

      Imaging

      Patients underwent routine assessment of LV function with commonly accepted methods. In this study, this included echocardiography (n = 38), radionuclide angiography (n = 3), MRI (n = 1), or SPECT perfusion (n = 1).
      The PET imaging methods are detailed in previous reports and are in accordance with guidelines.
      • Beanlands R.S.B.
      • Ruddy T.D.
      • deKemp R.A.
      • et al.
      Positron emission tomography and recovery following revascularization (PARR-1): the importance of scar and the development of a prediction rule for the degree of recovery of left ventricular function.
      • O'Meara E.
      • Mielniczuk L.M.
      • Wells G.A.
      • et al.
      Alternative Imaging Modalities in Ischemic Heart Failure (AIMI-HF) IMAGE HF Project I-A: study protocol for a randomized controlled trial.
      • Beanlands R.
      • Nichol G.
      • Ruddy T.D.
      • et al.
      Evaluation of outcome and cost-effectiveness using an FDG-PET-guided approach to management of patients with coronary disease and severe left ventricular dysfunction (PARR-2): rationale, design, and methods.
      • Dilsizian V.
      • Bacharach S.L.
      • Beanlands R.S.
      • et al.
      ASNC imaging guidelines/SNMMI procedure standard for positron emission tomography (PET) nuclear cardiology procedures.
      All PET images were acquired using either the GE Discovery 690 PET/VCT or the GE Discovery 600 PET/CT (GE Healthcare, Aurora, OH) scanners. PET perfusion imaging was acquired at rest with a standard protocol using 82Rb or 13N-ammonia, as described previously.
      • Beanlands R.S.B.
      • Ruddy T.D.
      • deKemp R.A.
      • et al.
      Positron emission tomography and recovery following revascularization (PARR-1): the importance of scar and the development of a prediction rule for the degree of recovery of left ventricular function.
      • O'Meara E.
      • Mielniczuk L.M.
      • Wells G.A.
      • et al.
      Alternative Imaging Modalities in Ischemic Heart Failure (AIMI-HF) IMAGE HF Project I-A: study protocol for a randomized controlled trial.
      • Beanlands R.
      • Nichol G.
      • Ruddy T.D.
      • et al.
      Evaluation of outcome and cost-effectiveness using an FDG-PET-guided approach to management of patients with coronary disease and severe left ventricular dysfunction (PARR-2): rationale, design, and methods.
      • Dilsizian V.
      • Bacharach S.L.
      • Beanlands R.S.
      • et al.
      ASNC imaging guidelines/SNMMI procedure standard for positron emission tomography (PET) nuclear cardiology procedures.
      For FDG imaging, patients without diabetes were studied after an oral glucose load, whereas an insulin-euglycemic clamp was used for those with diabetes.
      • Beanlands R.S.B.
      • Ruddy T.D.
      • deKemp R.A.
      • et al.
      Positron emission tomography and recovery following revascularization (PARR-1): the importance of scar and the development of a prediction rule for the degree of recovery of left ventricular function.
      • O'Meara E.
      • Mielniczuk L.M.
      • Wells G.A.
      • et al.
      Alternative Imaging Modalities in Ischemic Heart Failure (AIMI-HF) IMAGE HF Project I-A: study protocol for a randomized controlled trial.
      • Beanlands R.
      • Nichol G.
      • Ruddy T.D.
      • et al.
      Evaluation of outcome and cost-effectiveness using an FDG-PET-guided approach to management of patients with coronary disease and severe left ventricular dysfunction (PARR-2): rationale, design, and methods.
      • Dilsizian V.
      • Bacharach S.L.
      • Beanlands R.S.
      • et al.
      ASNC imaging guidelines/SNMMI procedure standard for positron emission tomography (PET) nuclear cardiology procedures.
      • Vitale G.D.
      • deKemp R.A.
      • Ruddy T.D.
      • Williams K.
      • Beanlands R.S.
      Myocardial glucose utilization and optimization of (18)F-FDG-PET imaging in patients with non-insulin-dependent diabetes mellitus, coronary artery disease, and left ventricular dysfunction.

      PET data analysis and interpretation

      An automated method of image analysis (FlowQuant software; UOHI) was applied to the perfusion/FDG-PET data to yield quantified measures of the extent and severity of perfusion/FDG mismatch as a measure of myocardial hibernation and perfusion/FDG match as a measure of scar, as previously described.
      • Beanlands R.S.B.
      • Nichol G.
      • Huszti E.
      • et al.
      F-18-fluorodeoxyglucose positron emission tomography imaging-assisted management of patients with severe left ventricular dysfunction and suspected coronary disease: a randomized, controlled trial (PARR-2).
      • Beanlands R.S.B.
      • Ruddy T.D.
      • deKemp R.A.
      • et al.
      Positron emission tomography and recovery following revascularization (PARR-1): the importance of scar and the development of a prediction rule for the degree of recovery of left ventricular function.
      • Klein R.
      • Renaud J.M.
      • Ziadi M.C.
      • et al.
      Intra- and inter-operator repeatability of myocardial blood flow and myocardial flow reserve measurements using rubidium-82 PET and a highly automated analysis program.
      Match (scar) and mismatch (hibernation) are expressed as a percentage of the left ventricle, as previously described and as illustrated in Figures 1 and 2.
      • Beanlands R.S.B.
      • Nichol G.
      • Huszti E.
      • et al.
      F-18-fluorodeoxyglucose positron emission tomography imaging-assisted management of patients with severe left ventricular dysfunction and suspected coronary disease: a randomized, controlled trial (PARR-2).
      • Beanlands R.S.B.
      • Ruddy T.D.
      • deKemp R.A.
      • et al.
      Positron emission tomography and recovery following revascularization (PARR-1): the importance of scar and the development of a prediction rule for the degree of recovery of left ventricular function.
      In addition, all scans were reviewed by an imaging expert. The expert considered the qualitative images along with the quantitative polar map data and assigned a semiquantitative category for scar and hibernation as none (0%-5%), mild (5%-10%), moderate (10%-20%), or severe (> 20%), which is included in the predefined image case report form and also the clinical report (http://www.image-hf.ca/PDFs/HF12_ViabiltyPETSPECT.pdf).
      • O'Meara E.
      • Mielniczuk L.M.
      • Wells G.A.
      • et al.
      Alternative Imaging Modalities in Ischemic Heart Failure (AIMI-HF) IMAGE HF Project I-A: study protocol for a randomized controlled trial.
      For the purposes of this study, moderate and severe were combined to represent ≥ 10% as a mid-semiquantitative category. This was predefined for this analysis and considered reasonable considering previously published literature applying this clinically significant cut point for definition of hibernation and scar.
      • Ling L.F.
      • Marwick T.H.
      • Flores D.R.
      • et al.
      Identification of therapeutic benefit from revascularization in patients with left ventricular systolic dysfunction: inducible ischemia versus hibernating myocardium.
      • Hachamovitch R.
      • Rozanski A.
      • Shaw L.J.
      • et al.
      Impact of ischaemia and scar on the therapeutic benefit derived from myocardial revascularization vs. medical therapy among patients undergoing stress-rest myocardial perfusion scintigraphy.
      Figure thumbnail gr1
      Figure 1Example of perfusion and fluorodeoxyglucose–positron emission tomography images in a patient with moderate scar (13% of left ventricle) and significant mismatch (27% of left ventricle) in the inferior, inferolateral, anterior, anteroseptal, and apical walls. The patient's high-sensitivity cardiac troponin and N-terminal pro b-type natriuretic peptide levels were high (489.7 pg/mL and 32,032 pg/mL, respectively). Left: Perfusion; Right: FDG. HLA, horizontal long-axis planes; SOA, short axis; VLA, vertical long axis.
      Figure thumbnail gr2
      Figure 2Example of perfusion and fluorodeoxyglucose–positron emission tomography images in a patient with predominant scar (35%) in the anterior, septal, anterolateral, and apical walls of the left ventricle and nonsignificant mismatch (1.2%). The patient's high-sensitivity cardiac troponin and N-terminal pro b-type natriuretic peptide levels were low (8.34 pg/mL and 1997 pg/mL, respectively). HLA, horizontal long-axis planes; SOA, short axis; VLA, vertical long axis.

      Blood biochemistry

      Before PET imaging, blood samples were procured from all patients and stored at −80°C for later analysis. Serum high-sensitivity cardiac troponin (hs-cTnT) (Roche Diagnostics, Indianapolis, IN) and NT-proBNP (Roche Diagnostics) were measured using commercially available US Food and Drug Administration–approved electrochemiluminescence immunoassays with a Roche Cobas e411 analyzer. The normal limit for the hs-cTnT is < 99th percentile (< 14 ng/L).
      • Sanchis J.
      • García-Blas S.
      • Carratalá A.
      • et al.
      Clinical evaluation versus undetectable high-sensitivity troponin for assessment of patients with acute chest pain.
      • Xu R.-Y.
      • Zhu X.-F.
      • Yang Y.
      • Ye P.
      High-sensitive cardiac troponin T.
      This discriminatory 99th percentile is designated as the decision level for the diagnosis of MI.
      • Thygesen K.
      • Alpert J.S.
      • Jaffe A.S.
      • et al.
      Third universal definition of myocardial infarction.
      NT-proBNP cutoffs have been validated to diagnose acute HF. An age-independent cut point of 300 pg/mL had a 98% negative predictive value for excluding acute HF.
      • Januzzi J.L.
      • van Kimmenade R.
      • Lainchbury J.
      • et al.
      NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: an international pooled analysis of 1256 patients: the International Collaborative of NT-proBNP Study.

      Statistical analysis

      Statistical analyses and graphic representations were performed using Stata 14 (Stata LLC, College Station, TX) and Graphpad Prism 6.0 (GraphPad Software, San Diego, CA). Log-transformed hs-cTnT and NT-proBNP levels were used because their distributions were not normal. A Student t test was used to detect statistical differences between < 10% and ≥ 10% scar and hibernation. Pearson correlation coefficients were used to determine the degree of association between variables. The diagnostic performance (ie, the detection of ≥ 10% hibernation) of each biomarker was represented with receiver operator characteristic (ROC) curves and the area under the curve (AUC). Youden's index was used to identify the ROC optimal cutoff. We performed a secondary post hoc analysis evaluating hibernation in patients with ≥ 10% scar (n = 29). This cutoff was selected based on its being the midpoint of the predefined semiquantitative categories as well as on previous literature that used 10% to define extensive scar.
      • Hachamovitch R.
      • Rozanski A.
      • Shaw L.J.
      • et al.
      Impact of ischaemia and scar on the therapeutic benefit derived from myocardial revascularization vs. medical therapy among patients undergoing stress-rest myocardial perfusion scintigraphy.
      Multivariable analyses using logistical and multiple regressions were used to evaluate the relationship of NT-proBNP or hs-cTnT and hibernation/scar, adjusting for age, EF, and estimated glomerular filtration rate (eGFR) because these are known to be parameters that may affect NT-proBNP or hs-cTnT, or both.
      • Ibrahim N.
      • Januzzi J.L.
      The potential role of natriuretic peptides and other biomarkers in heart failure diagnosis, prognosis and management.
      • Gore M.O.
      • Seliger S.L.
      • Defilippi C.R.
      • et al.
      Age- and sex-dependent upper reference limits for the high-sensitivity cardiac troponin T assay.
      • Redfield M.M.
      • Rodeheffer R.J.
      • Jacobsen S.J.
      • et al.
      Plasma brain natriuretic peptide concentration: impact of age and gender.
      • Wang A.Y.-M.
      • Lai K.-N.
      Use of cardiac biomarkers in end-stage renal disease.
      • Wiley C.L.
      • Switzer S.P.
      • Berg R.L.
      • Glurich I.
      • Dart R.A.
      Association of B-type natriuretic peptide levels with estimated glomerular filtration rate and congestive heart failure.
      P values < 0.05 were considered statistically significant.

      Results

      Baseline characteristics

      There were 43 consecutive eligible patients who underwent FDG-PET imaging and had blood sampling for biomarkers for the study. Two patients could not complete the imaging because of claustrophobia and were excluded. Two patients were noted to be on dialysis and were thus excluded, giving a final sample of 39 patients with complete analyzable data who were included in this study. Baseline characteristics appear in Table 1. The NT-proBNP levels ranged from 151.3-22,823 pg/mL, with a mean of 3706.7 ± 4288.7 pg/mL (median with interquartile range [IQR], 1997 pg/mL [range, 1024.5-5359.5 pg/mL]). Hs-cTnT levels ranged from 4.17-4947 mg/mL, with a mean of 178.4 ± 787.7 pg/mL (median [IQR], 34.48 pg/mL [range, 18.12-43.02 pg/mL]). Overall, on the FDG-PET study, 29 patients had significant (≥ 10%) scar, and 7 patients had significant (≥ 10%) hibernation. There were 8 patients who had no significant (≥ 10%) scar or hibernation, and 5 patients who had both.
      Table 1Patient characteristics
      Clinical characteristics (n = 39)
      Age (y)67.2 ± 7.9
      Sex (male)33 (85%)
      Diabetes mellitus25 (64%)
      Hypertension28 (72%)
       Systolic blood pressure (mm Hg)120.3 ± 18.6
       Diastolic blood pressure (mm Hg)68.8 ± 12.4
      Hyperlipidemia28 (72%)
      Smoking24 (62%)
      Family history of premature CAD15 (38%)
      Chronic renal dysfunction (eGFR < 60)10 (26%)
       eGFR (mL/min/1.73 m2)78.8 ± 34.2
       Creatinine (μM)107.1 ± 41.9
      Peripheral vascular disease4 (10%)
      Pulmonary disease12 (31%)
      Cerebrovascular disease5 (13%)
      Body mass index, kg/m228.2 ± 4.5
      Previous myocardial infarction27 (69%)
      Previous PCI12 (31%)
      Previous CABG2 (5%)
      Ejection fraction27.9 ± 8.5%
      NYHA class
       I0 (0%)
       II20 (50%)
       III18 (45%)
       IV1 (2.5%)
      Medications
       β-Blocker35 (90%)
       ACE inhibitor or ARB36 (92%)
       Aldosterone antagonist10 (26%)
       Statin drug35 (90%)
       Digoxin4 (10%)
       Antiplatelet or anticoagulant37 (95%)
      Biomarkers
       NT-proBNP (pg/mL)
      Mean ± SD3706.7 ± 4288.7
      Median (IQR)1997 (1024.5-5359.5)
       Hs-cTnT (pg/mL)
      Mean ± SD178.4 ± 787.7
      Median (IQR)34.48 (18.12-43.02)
      Data expressed as mean ± SD or mean (%).
      ACE, angiotensin-converting enzyme; ARB, angiotensin-receptor blocker; CABG, coronary artery bypass grafting; CAD, coronary artery disease; eGFR, estimated glomerular filtration rate; Hs-cTnT, high-sensitivity cardiac troponin T; IQR, interquartile range; NT-proBNP, N-terminal pro b-type natriuretic peptide; PCI, percutaneous coronary intervention; SD, standard deviation.

      Relationships of biomarkers to LV hibernation

      Both NT-proBNP and hs-cTnT levels were significantly elevated in patients with > 10% hibernation (≥ 10% hibernation: mean ± standard deviation [SD], 7419.1 ± 7169.5 pg/mL vs < 10% hibernation: mean ± SD, 2894.6 ± 2967.4 for NT-proBNP; P < 0.05) and (≥ 10% hibernation: mean ± SD, 789.3 ± 1835.3 pg/mL vs < 10% hibernation: mean ± SD, 44.8 ± 78.9 pg/mL for hs-cTnT; P < 0.01) (Fig. 3, A and B ). NT-proBNP was significantly related to the presence of ≥ 10% hibernation after adjustment for age, eGFR, and EF (P < 0.05). In this model, hs-cTnT approached statistical significance (P = 0.06) (Table 2).
      Figure thumbnail gr3
      Figure 3(A, C, and E) Log of serum N-terminal pro b-type natriuretic peptide (NT-proBNP) and (B, D, and F) high-sensitivity cardiac troponin T (hs-cTnT) concentrations in patients with varying left ventricular (LV) hibernation severity. A and B compare patients with and those without significant (> 10%) hibernation. Median (interquartile range) values of (A) serum NT-proBNP and (B) hs-cTnT levels are shown at the top of each corresponding bar. C and D plot the relationship of the (C) log serum NT-proBNP and (D) hs-cTnT vs the percentage LV hibernation on quantitative analysis. E and F plot the relationships between (E) log serum NT-proBNP and (F) hs-cTnT and levels with percentage of LV hibernation in a subgroup of patients (n = 29) with the presence of significant (≥ 10%) scar. Data are expressed as mean ± standard deviation. P < 0.05; ∗∗P < 0.01.
      Table 2Logistic regression analysis between the presence of hibernation and clinical variables including log NT-proBNP and log hs-cTnT
      VariableOdds ratioSEz scoreP value95% CI
      > 10% hibernation
       Log hs-cTnT8.579.871.860.0620.90-82.00
       Age0.860.06−2.060.0390.74-0.99
       eGFR0.980.019−0.860.3900.94-1.02
       EF1.030.0740.410.6810.89-1.19
      > 10% hibernation
       Log NT-proBNP8.8318.332.160.0310.15-515.59
       Age0.820.076−2.120.0340.69-0.98
       eGFR0.980.02−1.030.3050.93-1.02
       EF1.230.161.660.0970.96-1.58
      Age (per 1-y increase), eGFR (per 1 mL/min/1.73 m2 increase), EF (per 1% increase); log hs-cTnT (per 1 increase in logged values), log NT-pro-BNP (per 0.1 increase in logged values).
      CI, confidence interval; EF, ejection fraction; eGFR, estimated glomerular filtration rate; Hs-cTnT, high-sensitivity cardiac troponin T; NT-proBNP, N-terminal pro b-type natriuretic peptide; SE, standard error.
      The ROC curve analysis for the detection of > 10% hibernation of the myocardium for NT-proBNP and hs-cTnT is shown in Figure 4. The ROC of the AUC value for NT-proBNP and hs-cTnT was 0.75 (95% confidence interval [CI], 0.54-0.97; P = 0.03) and 0.78 (95% CI, 0.56-1.01; P = 0.02), respectively. The analysis showed an optimal cutoff for NT-proBNP of > 3066 pg/mL (sensitivity, 86%; specificity, 72%) and an optimal cutoff for hs-cTnT of > 66 pg/mL (sensitivity, 71%; specificity, 94%) (Fig. 4).
      Figure thumbnail gr4
      Figure 4Receiver operator characteristic curve analysis for both (A) N-terminal pro b-type natriuretic peptide (NT-proBNP) and (B) high-sensitivity cardiac troponin T (hs-cTnT). The optimal cutoff for the detection of > 10% hibernation was 3066 pg/mL for NT-proBNP and 66 pg/mL for hs-cTnT.
      There was a continuous relationship between increasing degrees of hibernation and increasing NT-proBNP and hs-cTnT levels (Fig. 4, C and D). Hs-cTnT levels increased with the degree of LV hibernation. There was a statistically significant relationship between log hs-cTnT and percent hibernation (r = 0.57; P < 0.001; 95% CI, 3.15-9.01) (Fig. 3D). Furthermore, the multivariable regression analysis confirmed that hs-cTnT (regression coefficient, 5.55; P < 0.001; 95% CI, 2.48-8.61) and age (regression coefficient, −0.22; P < 0.05; 95% CI, −0.44 to 0.0036) were independently correlated with hibernation after adjusting for eGFR and EF (Table 3).
      Table 3Multivariable regression analysis between left ventricular hibernation (%) and clinical variables including log NT-proBNP and log hs-cTnT
      VariableRegression coefficientSEt testP value95% CI
      Model 1: NT-proBNP
       Log NT-proBNP3.612.201.640.110−0.86 to 8.08
       Age−0.230.12−1.920.064−0.48 to 0.014
       eGFR−0.0540.031−1.750.089−0.12 to 0.0088
       EF0.220.121.880.068−0.017 to 0.45
      Model 2: hs-cTnT
       Log hs-cTnT5.551.513.680.0012.48 to 8.61
       Age−0.220.11−2.070.047−0.44 to 0.0036
       eGFR−0.0400.027−1.490.146−0.094 to 0.015
       EF0.110.0941.120.269−0.085 to 0.30
      CI, confidence interval; EF, ejection fraction; eGFR, estimated glomerular filtration rate; Hs-cTnT, high-sensitivity cardiac troponin T; NT-proBNP, N-terminal pro b-type natriuretic peptide; SE, standard error.

      Relationships of biomarkers to LV scar

      NT-proBNP and hs-cTnT levels were similar in patients with moderate-severe scar (≥ 10%) compared with patients with scar < 10% (Fig. 5, A-C ). There was also no statistically significant correlation between LV scar and either NT-proBNP (r = −0.05; P = 0.78; 95% CI, −8.14 to 6.12) or hs-cTnT (r = −0.10; P = 0.54; 95% CI, −8.19 to 4.36) (Fig. 5, B-D).
      Figure thumbnail gr5
      Figure 5(A, B) Log of the serum N-terminal pro b-type natriuretic peptide (NT-proBNP) and (C, D) high-sensitivity cardiac troponin T (hs-cTnT) concentrations in patients with varying left ventricular (LV) scar severity. A and C compare patients with and those without significant (> 10%) scar. Median (interquartile range) values of serum (A) NT-proBNP and (C) hs-cTnT levels are shown at the top of each corresponding bar. C and D plot the relationship of the log serum (B) NT-proBNP and (D) hs-cTnT vs the percentage of LV scar on quantitative analysis. Data are expressed as mean ± standard deviation.

      Biomarker relationships to hibernating myocardium in patients with scar

      To elucidate whether the relationships between hs-cTnT and NT-proBNP levels with hibernation were affected in the presence of significant (≥ 10%) scar, a post hoc analysis was conducted in this patient subgroup (n = 29). In patients with significant scar, both hs-cTnT and NT-proBNP levels increased as the degree of LV hibernation increased. Log NT-proBNP (r = 0.45; P = 0.01; 95% CI, 1.21-9.82) and log hs-cTnT (r = 0.73; P < 0.0001; 95% CI, 4.56-9.91) significantly correlated with percentage of LV hibernation (Fig. 3, E and F). Furthermore, the multivariable regression analysis revealed that NT-proBNP (regression coefficient, 6.39; P = 0.02; 95% CI, 1.01-11.77) and hs-cTnT (regression coefficient, 7.27; P < 0.0001; 95% CI, 4.19-10.35) were independently correlated with LV hibernation and not with scar. The adjusted model in Table 4 summarizes that the interaction between LV hibernation and either NT-proBNP or hs-cTnT is still statistically significant after adjusting for eGFR, EF, and age.
      Table 4Multivariate regression analysis between left ventricular hibernation (%) and clinical variables including log NT-proBNP and log hs-cTnT in patients with significant scar (> 10%)
      VariableRegression coefficientSEt testP value95% CI
      Model 1: NT-proBNP
       Log NT-proBNP6.392.612.450.0221.01 to 11.77
       Age−0.140.18−0.800.429−0.50 to 0.22
       eGFR−0.0220.038−0.580.567−0.099 to 0.056
       EF0.190.131.490.149−0.073 to 0.45
      Model 2: hs-cTnT
       Log hs-cTnT7.271.494.87< 0.00014.19 to 10.35
       Age−0.120.14−0.860.400−0.41 to 0.17
       eGFR−0.00840.029−0.290.774−0.068 to 0.051
       EF0.0160.0980.160.871−0.19 to 0.22
      CI, confidence interval; EF, ejection fraction; eGFR, estimated glomerular filtration rate; hs-cTnT, high-sensitivity cardiac troponin T; NT-proBNP, N-terminal pro b-type natriuretic peptide; SE, standard error.

      Relationships of biomarkers to GFR and EF

      Linear regression analyses were performed between serum NT-proBNP or hs-cTnT and renal and LV function and were evaluated with eGFR and EF, respectively. Both NT-proBNP (r = −0.42; P < 0.01; 95% CI, −50.58 to −8.89) and hs-cTnT (r = −0.35; P < 0.05; 95% CI, −41.03 to −2.31) were negatively correlated with eGFR. There was a significant negative correlation between NT-proBNP and EF (r = −0.42; P < 0.01; 95% CI, −12.54 to −2.15); however, hs-cTnT was not correlated with EF (r = 0.04; P = 0.82; 95% CI, −4.54 to 5.72).

      Discussion

      This study demonstrates that serum levels of NT-proBNP and hs-cTnT are elevated in stable patients with moderate-severe levels of hibernating myocardium and LV dysfunction or HF. The biomarker levels correlated with the extent of hibernation independent of EF, age, and eGFR in ischemic cardiomyopathy (in particular in patients with ≥ 10% scar). Furthermore, a level of NT-proBNP > 3066 pg/mL or hs-cTnT > 66 pg/mL had reasonable diagnostic value for the detection of significant hibernation. NT-proBNP and hs-cTnT levels were not correlated with the extent of scar in these patients. Taken together, these data support the novel concept that both the severity and extent of LV hibernation are determinants of serum NT-proBNP and hs-cTnT elevation in patients with ischemic HF, rather than the extent of pre-existing myocardial damage or scar, extending the traditional variables related to EF and the severity of LV dysfunction.
      Patients with ischemic HF are often considered for revascularization therapy.
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      An approach to the rational use of revascularization in heart failure patients.
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      ASNC imaging guidelines/SNMMI procedure standard for positron emission tomography (PET) nuclear cardiology procedures.
      However, controversy remains, because other studies suggest that image-guided strategies may not yield definitive clinical benefit in this population.
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      The current study is the first step toward understanding the unique information content of NT-proBNP and hs-cTnT in the context of viability imaging and ischemic HF. This will help to determine whether a biomarker-guided approach can complement the current image-guided strategy for clinical decision-making in patients with ischemic HF. Future studies are needed to determine whether NT-proBNP and hs-cTnT levels, obtained before or in combination with viability imaging, can better predict outcome benefits in patients with ischemic HF after revascularization and thus enable a more precision targeted patient selection process.
      It is now well established that BNP levels are chronically elevated in patients with ischemic HF.
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      To our knowledge, only 1 previous study has suggested a correlation between BNP and hibernation as measured with cardiac MRI and dobutamine echocardiography. In this study, the BNP levels were assessed in patients with recent MI, NYHA functional class I-II dyspnea, and mild reductions in LVEF (48% ± 15%).
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      They observed a moderate correlation between log BNP levels and indices of viable myocardium and scar. Differences in patient selection (recent MI and mild LV dysfunction) may explain the heterogeneity in results when compared with this study. In contrast, our study included patients with much more significant LV dysfunction (mean, 27.8%) and thus a greater dynamic range of both biomarkers and extent of scar or hibernation; it was also a potentially more relevant population for defining viability when revascularization decisions are more difficult.
      • Mielniczuk L.M.
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      Does imaging-guided selection of patients with ischemic heart failure for high risk revascularization improve identification of those with the highest clinical benefit? Imaging-guided selection of patients with ischemic heart failure for high-risk revascularization improves identification of those with the highest clinical benefit.
      There is no consensus in the literature on the relationship between BNP or cTnT and scar in this patient population. Studies have reported that BNP levels decrease,
      • Aktas M.K.
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      do not change,
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      or increase in patients with stable scar.
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      Unrecognized myocardial scars detected by delayed-enhanced MRI are associated with increased levels of NT-proBNP.
      The heterogeneity of the results in the literature may be explained by the differences in patient populations, as well as timing after MI. Aktas et al.
      • Aktas M.K.
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      • et al.
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      found decreased BNP levels in patients with a large proportion of scar (> 33%), as evaluated in a relatively homogeneous population of patients with ischemic HF with EF < 35%, similar to our study. Our data showed that there was no difference in NT-proBNP and hs-cTnT levels between patients with and those without moderate-severe scar. Together these data support the suggestion by Atkas et al.
      • Aktas M.K.
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      • Jaber W.A.
      • et al.
      Relation of brain natriuretic peptide level to extent of left ventricular scarring in patients with chronic heart failure secondary to ischemic cardiomyopathy.
      that areas with significant scar “may lack the cellular biomachinery required” for this peptide.
      The current study also demonstrated that the relationship between NT-proBNP or hs-TnT and hibernation remains in patients with significant scar. That is, patients with significant scar and hibernation had markedly elevated BNP and cTnT levels. Further, in patients with moderate-severe scar, both BNP and cTnT levels were independently correlated with the degree of hibernation after adjusting for EF, eGFR, and age. Although speculative, it is plausible that hs-cTnT elevation in patients with hibernation, rather than scar, results from continued cell death, raising the need for early revascularization in this patient population. The improved relationship between BNP or cTnT levels and hibernation severity in patients with scar (≥ 10%) may result from the increased tension and stress on the remaining myocardium in the presence of a significant scar, inducing further production and release of cardiac stress peptides such as BNP and cTnT, especially from the hibernating myocardium. One may speculate that the ischemic but viable hibernating myocardium is thus doubly stressed with additional hemodynamic stimulus, thus further increasing the biomarker levels in the circulation. Further studies are required to support this hypothesis.
      The release of hs-cTnT in HF, when acute coronary syndromes have been excluded, has been attributed to a supply-demand mismatch, increased myocyte turnover with progressive myocardial dysfunction or subendocardial ischemic injury caused by wall stress (or both), myocardial apoptosis, and oxidative injury.
      • Wu A.H.
      Increased troponin in patients with sepsis and septic shock: myocardial necrosis or reversible myocardial depression?.
      • Narula J.
      • Pandey P.
      • Arbustini E.
      • et al.
      Apoptosis in heart failure: release of cytochrome c from mitochondria and activation of caspase-3 in human cardiomyopathy.
      • Jhund P.S.
      • Claggett B.L.
      • Voors A.A.
      • et al.
      Elevation in high-sensitivity troponin T in heart failure and preserved ejection fraction and influence of treatment with the angiotensin receptor neprilysin inhibitor LCZ696.
      • Gravning J.
      • Askevold E.T.
      • Nymo S.H.
      • et al.
      Prognostic effect of high-sensitive troponin T assessment in elderly patients with chronic heart failure: results from the CORONA trial.
      • Latini R.
      • Masson S.
      • Anand I.S.
      • et al.
      Prognostic value of very low plasma concentrations of troponin T in patients with stable chronic heart failure.
      Given the proposed mechanism for hibernation as metabolic and functional downregulation secondary to repeated ischemia, it is logical to surmise that hs-cTnT release would relate to the degree of hibernation. However, despite the known pathophysiological mechanisms for troponin elevation, studies evaluating its relationship to myocardial hibernation have been limited to date. The current study may represent 1 of the first reports that hs-cTnT levels in patients with ischemic HF relate to the degree of hibernation.
      Regarding natriuretic peptides, recent evidence indicates that they are secreted in hypoxic, ischemic, or hibernating myocardium, or a combination, in addition to the known responses to volume and pressure load.
      • Moe G.W.
      • Ezekowitz J.A.
      • O'Meara E.
      • et al.
      The 2014 Canadian Cardiovascular Society heart failure management guidelines focus update: anemia, biomarkers, and recent therapeutic trial implications.
      • Ibrahim N.
      • Januzzi J.L.
      The potential role of natriuretic peptides and other biomarkers in heart failure diagnosis, prognosis and management.
      • Goetze J.P.
      • Christoffersen C.
      • Perko M.
      • et al.
      Increased cardiac BNP expression associated with myocardial ischemia.
      • May D.
      • Gilon D.
      • Djonov V.
      • et al.
      Transgenic system for conditional induction and rescue of chronic myocardial hibernation provides insights into genomic programs of hibernation.
      Goetze et al.
      • Goetze J.P.
      • Christoffersen C.
      • Perko M.
      • et al.
      Increased cardiac BNP expression associated with myocardial ischemia.
      demonstrated that plasma BNP and proBNP were markedly increased in patients with CAD undergoing revascularization, even without LV dysfunction, and were strongly associated with LV tissue BNP mRNA expression. May et al.,
      • May D.
      • Gilon D.
      • Djonov V.
      • et al.
      Transgenic system for conditional induction and rescue of chronic myocardial hibernation provides insights into genomic programs of hibernation.
      using a transgenic model of myocardial hibernation, showed that BNP expression was strongly induced in LV cardiomyocytes coinciding with regions of cellular hypoxemia and hibernation. The authors further demonstrated that reversal of hibernation was accompanied by downregulation of myocardial BNP expression to control levels.
      Based on this previous research and the current results, one may speculate that the ischemic but viable hibernating myocardium is doubly stressed with additional hemodynamic stimulus, thus further increasing the biomarker levels in the circulation. Further research is required to support this hypothesis and to further understand the mechanisms for BNP and troponin release in patients with hibernating myocardium.

      Study limitations

      The modest sample size is a limitation of the present study. However, our sample size is similar to other related studies in the field to date and can alert the reader to further investigation in this field.
      • Nelson C.A.
      • Case C.
      • McCrohon J.
      • Marwick T.H.
      Relationship of extent and nature of dysfunctional myocardium to brain natriuretic peptide in patients with ischemic left ventricular dysfunction.
      A small sample size can pose a risk of overfitting a logistic regression model. To address this potential limitation, we also analyzed and displayed the data as continuous variables.
      The differences in hs-TnT and NT-proBNP levels for hibernating myocardium were significant and yielded promising AUC values in ROC analysis. The correlation between the level of hibernation with the level of hs-cTnT was significant, with a reasonable r value of 0.57, and the correlation with the level of NT-proBNP showed a trend that did not reach statistical significance, with a modest r value of 0.27 (Fig. 3). These relationships were numerically better and statistically significant when patients with scar ≥ 10% were considered (r values of 0.73 and 0.45, respectively). However, as a post hoc analysis, this should be interpreted with caution. Further studies are required to support these findings and are ongoing.
      Another study limitation was the lack of direct patient outcomes, especially related to revascularization. This will be followed up separately in the future as part of an ongoing prospective trial and is beyond of the scope of the current study.
      • O'Meara E.
      • Mielniczuk L.M.
      • Wells G.A.
      • et al.
      Alternative Imaging Modalities in Ischemic Heart Failure (AIMI-HF) IMAGE HF Project I-A: study protocol for a randomized controlled trial.

      Conclusions

      These data support the novel concept that both the presence and extent of LV hibernation influence NT-proBNP and hs-cTnT release in patients with ischemic HF and LV dysfunction, without influence from the extent of scar. This new insight puts these biomarkers in a new light in the setting of suspected ischemic HF. Future studies are needed to confirm these findings and to devise means to evaluate new strategies to complement current imaging approaches to identify patients who are most likely to benefit from revascularization.

      Acknowledgements

      The authors express their gratitude to the patients who have enrolled in the study and to the hard work of the research coordinators who have recruited the patients—Ermina Moga, CCRP and Debra Williams, RPN; the imaging and data analysis team—Jennifer Renaud, MSc and My-Linh Tran, MSc; and the PET imaging team—May Aung, CNMT, Kim Gardner, CNMT, Pat Grant, RN, and Laurie Camrass, RN; and the biomarker analysis team.

      Funding Sources

      This study was supported in part by a Canadian Institute for Health Research (CIHR) team grant (IMAGE-HF; grant No. CIF 99470), Genome Canada Grant (GAPP Program on Biomarker Discovery to P.P.L.) and CIHR Project Grant on novel biomarkers and target in heart failure (P.P.L.). J. Z. is an MD/PhD student supported in part by the Vanier Canada Graduate Scholarship, The University of Ottawa and by a government/industry grant from the Ontario Research Fund (ORF RE07-021) (industry partners Lantheus Medical Imaging and Jubilant DraxImage). R.B. is a career investigator supported by the Heart and Stroke Foundation of Ontario (HSFO) and is a tier 1 chair in cardiac imaging research at the University of Ottawa and the Vered Chair in Cardiology at the University of Ottawa Heart Institute. L.M. is a midcareer clinician scientist supported by HSFO and a tier 2 chair in HF research at the University of Ottawa.

      Disclosures

      R.D. is a consultant for, and has received grant funding from, Jubilant DraxImage; receives revenues from rubidium-82 generator technology licensed to Jubilant DraxImage and from sales of FlowQuant software. R.S.B. is or has been a consultant for, and has received grant funding from, GE Healthcare, Lantheus Medical Imaging, and Jubilant DraxImage. Roche Diagnostics Global is a partner with the Genome Canada grant to P.P.L. The other authors have no conflicts of interest to disclose.

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