Mitochondrial Integrity Is Critical in Right Heart Failure Development

Molecular processes underlying right ventricular (RV) dysfunction (RVD) and right heart failure (RHF) need to be understood to develop tailored therapies for the abatement of mortality of a growing patient population. Today, the armament to combat RHF is poor, despite the advancing identification of pathomechanistic processes. Mitochondrial dysfunction implying diminished energy yield, the enhanced release of reactive oxygen species, and inefficient substrate metabolism emerges as a potentially significant cardiomyocyte subcellular protagonist in RHF development. Dependent on the course of the disease, mitochondrial biogenesis, substrate utilization, redox balance, and oxidative phosphorylation are affected. The objective of this review is to comprehensively analyze the current knowledge on mitochondrial dysregulation in preclinical and clinical RVD and RHF and to decipher the relationship between mitochondrial processes and the functional aspects of the right ventricle (RV).

[1]  G. Du,et al.  Melatonin activates the Mst1-Nrf2 signaling to alleviate cardiac hypertrophy in pulmonary arterial hypertension. , 2022, European journal of pharmacology.

[2]  M. Humbert,et al.  2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. , 2022, European heart journal.

[3]  H. Milting,et al.  Right Heart Failure in Mice Upon Pressure Overload Is Promoted by Mitochondrial Oxidative Stress , 2022, JACC. Basic to translational science.

[4]  V. Agrawal,et al.  l‐Carnitine therapy improves right heart dysfunction through Cpt1‐dependent fatty acid oxidation , 2022, Pulmonary circulation.

[5]  P. Orchard,et al.  N-Acetylcysteine Reverses the Mitochondrial Dysfunction Induced by Very Long-Chain Fatty Acids in Murine Oligodendrocyte Model of Adrenoleukodystrophy , 2021, Biomedicines.

[6]  M. Mehrpooya,et al.  Oral N-acetylcysteine as an adjunct to standard medical therapy improved heart function in cases with stable class II and III systolic heart failure , 2021, Irish Journal of Medical Science (1971 -).

[7]  T. Thenappan,et al.  With No Lysine Kinase 1 Promotes Metabolic Derangements and RV Dysfunction in Pulmonary Arterial Hypertension , 2021, JACC. Basic to translational science.

[8]  H. Mannherz,et al.  The Interplay between S-Glutathionylation and Phosphorylation of Cardiac Troponin I and Myosin Binding Protein C in End-Stage Human Failing Hearts , 2021, Antioxidants.

[9]  S. Nekolla,et al.  Multimodal assessment of right ventricle overload-metabolic and clinical consequences in pulmonary arterial hypertension , 2021, Journal of Cardiovascular Magnetic Resonance.

[10]  Ingrid S. Lan,et al.  Transcriptomic and Functional Analyses of Mitochondrial Dysfunction in Pressure Overload‐Induced Right Ventricular Failure , 2021, Journal of the American Heart Association.

[11]  Taylor P Williams,et al.  Effect of Mitochondrial Antioxidant (Mito-TEMPO) on Burn Injury-Induced Cardiac Dysfunction. , 2021, Journal of the American College of Surgeons.

[12]  N. Trayanova,et al.  Hydrogen peroxide diffusion and scavenging shapes mitochondrial network instability and failure by sensitizing ROS-induced ROS release , 2020, Scientific Reports.

[13]  G. Hansmann,et al.  Emerging therapies for right ventricular dysfunction and failure. , 2020, Cardiovascular diagnosis and therapy.

[14]  V. Agrawal,et al.  Mechanistic Phase II Clinical Trial of Metformin in Pulmonary Arterial Hypertension , 2020, Journal of the American Heart Association.

[15]  G. Hansmann,et al.  Molecular mechanisms of right ventricular dysfunction in pulmonary arterial hypertension: focus on the coronary vasculature, sex hormones, and glucose/lipid metabolism. , 2020, Cardiovascular diagnosis and therapy.

[16]  V. Hjortdal,et al.  Increasing carbohydrate oxidation improves contractile reserves and prevents hypertrophy in porcine right heart failure , 2020, Scientific Reports.

[17]  G. Hansmann,et al.  Trans-right ventricle and transpulmonary metabolite gradients in human pulmonary arterial hypertension , 2020, Heart.

[18]  G. Fonarow,et al.  Effects of Elamipretide on Left Ventricular Function in Patients with Heart Failure with Reduced Ejection Fraction: The PROGRESS-HF Phase 2 Trial. , 2020, Journal of cardiac failure.

[19]  G. Hansmann,et al.  Activation of The Metabolic Master Regulator PPARγ - A Potential PIOneering Therapy for Pulmonary Arterial Hypertension. , 2020, American journal of respiratory cell and molecular biology.

[20]  J. Newman,et al.  BMPR2 dysfunction impairs insulin signaling and glucose homeostasis in cardiomyocytes. , 2019, American journal of physiology. Lung cellular and molecular physiology.

[21]  R. Metzger,et al.  Delineating the molecular and histological events that govern right ventricular recovery using a novel mouse model of PA de-banding. , 2019, Cardiovascular research.

[22]  K. Casali,et al.  Role of inflammation, oxidative stress, and autonomic nervous system activation during the development of right and left cardiac remodeling in experimental pulmonary arterial hypertension , 2019, Molecular and Cellular Biochemistry.

[23]  Yunliang Zang,et al.  Exploring Impaired SERCA Pump-Caused Alternation Occurrence in Ischemia , 2019, Comput. Math. Methods Medicine.

[24]  Resham Bhattacharya,et al.  Hydrogen sulfide signaling in mitochondria and disease , 2019, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[25]  M. Eghbali,et al.  Oxidative Stress and Its Implications in the Right Ventricular Remodeling Secondary to Pulmonary Hypertension , 2019, Front. Physiol..

[26]  N. Isern,et al.  Metabolic Response to Stress by the Immature Right Ventricle Exposed to Chronic Pressure Overload , 2019, Journal of the American Heart Association.

[27]  B. Ghanim,et al.  Disconnect between Fibrotic Response and Right Ventricular Dysfunction. , 2019, American journal of respiratory and critical care medicine.

[28]  A. Hickey,et al.  Mitochondrial function remains impaired in the hypertrophied right ventricle of pulmonary hypertensive rats following short duration metoprolol treatment , 2019, PloS one.

[29]  Yuichiro J. Suzuki,et al.  Ultrastructural Changes of the Right Ventricular Myocytes in Pulmonary Arterial Hypertension , 2019, Journal of the American Heart Association.

[30]  S. Archer,et al.  Biventricular Increases in Mitochondrial Fission Mediator (MiD51) and Proglycolytic Pyruvate Kinase (PKM2) Isoform in Experimental Group 2 Pulmonary Hypertension-Novel Mitochondrial Abnormalities , 2019, Front. Cardiovasc. Med..

[31]  S. Prabhu,et al.  Mitoquinone ameliorates pressure overload-induced cardiac fibrosis and left ventricular dysfunction in mice , 2019, Redox biology.

[32]  R. Schulz,et al.  Review on Chamber-Specific Differences in Right and Left Heart Reactive Oxygen Species Handling , 2018, Front. Physiol..

[33]  V. Agrawal,et al.  Adverse physiologic effects of Western diet on right ventricular structure and function: role of lipid accumulation and metabolic therapy , 2018, Pulmonary circulation.

[34]  S. Archer,et al.  Increased Drp1-Mediated Mitochondrial Fission Promotes Proliferation and Collagen Production by Right Ventricular Fibroblasts in Experimental Pulmonary Arterial Hypertension , 2018, Front. Physiol..

[35]  C. Maack,et al.  Metabolic remodelling in heart failure , 2018, Nature Reviews Cardiology.

[36]  B. O’Rourke,et al.  Mitochondrial ROS Drive Sudden Cardiac Death and Chronic Proteome Remodeling in Heart Failure , 2018, Circulation research.

[37]  G. Hansmann,et al.  PPARγ agonist pioglitazone reverses pulmonary hypertension and prevents right heart failure via fatty acid oxidation , 2018, Science Translational Medicine.

[38]  W. Seeger,et al.  Impact of the mitochondria-targeted antioxidant MitoQ on hypoxia-induced pulmonary hypertension , 2018, European Respiratory Journal.

[39]  M. Murphy,et al.  MitoQ improves mitochondrial dysfunction in heart failure induced by pressure overload , 2018, Free radical biology & medicine.

[40]  C. Tschöpe,et al.  Right ventricular strain in heart failure: Clinical perspective. , 2017, Archives of cardiovascular diseases.

[41]  Yuichiro J Suzuki,et al.  Oxidative profiling of the failing right heart in rats with pulmonary hypertension , 2017, PloS one.

[42]  Arantxa González,et al.  Phenotyping of myocardial fibrosis in hypertensive patients with heart failure. Influence on clinical outcome , 2017, Journal of hypertension.

[43]  R. Tian,et al.  Metabolism in cardiomyopathy: every substrate matters , 2017, Cardiovascular research.

[44]  S. Archer,et al.  Ischemia-induced Drp1 and Fis1-mediated mitochondrial fission and right ventricular dysfunction in pulmonary hypertension , 2017, Journal of Molecular Medicine.

[45]  C. Nediani,et al.  Monoamine Oxidase Is Overactivated in Left and Right Ventricles from Ischemic Hearts: An Intriguing Therapeutic Target , 2016, Oxidative medicine and cellular longevity.

[46]  D. Stewart,et al.  Shifts in myocardial fatty acid and glucose metabolism in pulmonary arterial hypertension: a potential mechanism for a maladaptive right ventricular response. , 2016, European heart journal cardiovascular Imaging.

[47]  J. Mascherbauer,et al.  Interstitial Fibrosis, Functional Status, and Outcomes in Heart Failure With Preserved Ejection Fraction: Insights From a Prospective Cardiac Magnetic Resonance Imaging Study , 2016, Circulation. Cardiovascular imaging.

[48]  W. Fang,et al.  Quantitative assessment of right ventricular glucose metabolism in idiopathic pulmonary arterial hypertension patients: a longitudinal study. , 2016, European heart journal cardiovascular Imaging.

[49]  R. Rodenburg,et al.  Mitochondrial complex I dysfunction and altered NAD(P)H kinetics in rat myocardium in cardiac right ventricular hypertrophy and failure. , 2016, Cardiovascular research.

[50]  C. Ottenheijm,et al.  Right Ventricular Myocardial Stiffness in Experimental Pulmonary Arterial Hypertension , 2016, Circulation. Heart failure.

[51]  Cheuk-Kwan Sun,et al.  Administration of antioxidant peptide SS-31 attenuates transverse aortic constriction-induced pulmonary arterial hypertension in mice , 2016, Acta Pharmacologica Sinica.

[52]  R. Gerszten,et al.  Fatty Acid Metabolic Defects and Right Ventricular Lipotoxicity in Human Pulmonary Arterial Hypertension , 2016, Circulation.

[53]  J. Bian,et al.  Hydrogen Sulfide and Cellular Redox Homeostasis , 2016, Oxidative medicine and cellular longevity.

[54]  P. Ferdinandy,et al.  Specific Mechanisms Underlying Right Heart Failure: The Missing Upregulation of Superoxide Dismutase-2 and Its Decisive Role in Antioxidative Defense. , 2015, Antioxidants & redox signaling.

[55]  D. Bernstein,et al.  Molecular Mechanisms of Right Ventricular Failure , 2015, Circulation.

[56]  W. Fang,et al.  The Prognostic Value of 18F-FDG Uptake Ratio Between the Right and Left Ventricles in Idiopathic Pulmonary Arterial Hypertension , 2015, Clinical nuclear medicine.

[57]  P. Lipp,et al.  Reversal of Mitochondrial Transhydrogenase Causes Oxidative Stress in Heart Failure. , 2015, Cell metabolism.

[58]  R. Wüst,et al.  Decreased creatine kinase is linked to diastolic dysfunction in rats with right heart failure induced by pulmonary artery hypertension , 2015, Journal of molecular and cellular cardiology.

[59]  B. Guida,et al.  NOX signaling in molecular cardiovascular mechanisms involved in the blood pressure homeostasis , 2015, Front. Physiol..

[60]  H. Krum,et al.  A Novel Hydrogen Sulfide Prodrug, SG1002, Promotes Hydrogen Sulfide and Nitric Oxide Bioavailability in Heart Failure Patients , 2015, Cardiovascular therapeutics.

[61]  A. Briasoulis,et al.  Myocardial fibrosis on cardiac magnetic resonance and cardiac outcomes in hypertrophic cardiomyopathy: a meta-analysis , 2015, Heart.

[62]  C. Zuurbier,et al.  Increased in vivo mitochondrial oxygenation with right ventricular failure induced by pulmonary arterial hypertension: mitochondrial inhibition as driver of cardiac failure? , 2015, Respiratory Research.

[63]  S. Gupte,et al.  Increased Reactive Oxygen Species, Metabolic Maladaptation, and Autophagy Contribute to Pulmonary Arterial Hypertension–Induced Ventricular Hypertrophy and Diastolic Heart Failure , 2014, Hypertension.

[64]  M. Humbert,et al.  N-acetylcysteine improves established monocrotaline-induced pulmonary hypertension in rats , 2014, Respiratory Research.

[65]  S. Matoba,et al.  Oxidative Post-Translational Modifications Develop LONP1 Dysfunction in Pressure Overload Heart Failure , 2014, Circulation. Heart failure.

[66]  H. Szeto,et al.  Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis , 2014, British journal of pharmacology.

[67]  H. Szeto First‐in‐class cardiolipin‐protective compound as a therapeutic agent to restore mitochondrial bioenergetics , 2014, British journal of pharmacology.

[68]  M. Friedberg,et al.  Right Versus Left Ventricular Failure: Differences, Similarities, and Interactions , 2014, Circulation.

[69]  L. Gleaves,et al.  Evidence for right ventricular lipotoxicity in heritable pulmonary arterial hypertension. , 2014, American journal of respiratory and critical care medicine.

[70]  H. Champion,et al.  Mitochondria in Cardiovascular Physiology and Disease Nox-derived ROS are acutely activated in pressure overload pulmonary hypertension : indications for a seminal role for mitochondrial Nox 4 , 2013 .

[71]  A. Trafford,et al.  Sarcoplasmic Reticulum Ca-ATPase and Heart Failure 20 Years Later , 2013, Circulation research.

[72]  H. Szeto,et al.  The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin. , 2013, Journal of the American Society of Nephrology : JASN.

[73]  A. Alzoubi,et al.  Dehydroepiandrosterone restores right ventricular structure and function in rats with severe pulmonary arterial hypertension. , 2013, American journal of physiology. Heart and circulatory physiology.

[74]  J. Sadoshima,et al.  Thioredoxin 1 Is Essential for Sodium Sulfide–Mediated Cardioprotection in the Setting of Heart Failure , 2013, Arteriosclerosis, thrombosis, and vascular biology.

[75]  D. Kass,et al.  Nitric oxide synthases in heart failure. , 2013, Antioxidants & redox signaling.

[76]  Tevfik F Ismail,et al.  Association of fibrosis with mortality and sudden cardiac death in patients with nonischemic dilated cardiomyopathy. , 2013, JAMA.

[77]  J. Dou,et al.  Theoretical investigation of the mechanism of heart failure using a canine ventricular cell model: especially the role of up-regulated CaMKII and SR Ca(2+) leak. , 2013, Journal of molecular and cellular cardiology.

[78]  S. Steinberg Oxidative Stress and Sarcomeric Proteins , 2013, Circulation research.

[79]  J. Bigbee,et al.  Metabolic Gene Remodeling and Mitochondrial Dysfunction in Failing Right Ventricular Hypertrophy Secondary to Pulmonary Arterial Hypertension , 2013, Circulation. Heart failure.

[80]  M. MacCoss,et al.  Global Proteomics and Pathway Analysis of Pressure-Overload–Induced Heart Failure and Its Attenuation by Mitochondrial-Targeted Peptides , 2012, Circulation. Heart failure.

[81]  Andres I Rodriguez,et al.  Chronic hypoxia induces right heart failure in caveolin-1-/- mice. , 2012, American journal of physiology. Heart and circulatory physiology.

[82]  R. Balaban,et al.  Homogenous protein programming in the mammalian left and right ventricle free walls. , 2011, Physiological genomics.

[83]  N. Westerhof,et al.  Right Ventricular Failure in Idiopathic Pulmonary Arterial Hypertension Is Associated With Inefficient Myocardial Oxygen Utilization , 2011, Circulation. Heart failure.

[84]  A. Einstein,et al.  PET Imaging May Provide a Novel Biomarker and Understanding of Right Ventricular Dysfunction in Patients With Idiopathic Pulmonary Arterial Hypertension , 2011, Circulation. Cardiovascular imaging.

[85]  P. D. del Nido,et al.  Impaired Mitochondrial Biogenesis Precedes Heart Failure in Right Ventricular Hypertrophy in Congenital Heart Disease , 2011, Circulation. Heart failure.

[86]  N. Ozdemir,et al.  Increased Right Ventricular Glucose Metabolism in Patients With Pulmonary Arterial Hypertension , 2011, Clinical nuclear medicine.

[87]  Roberta Menabò,et al.  Monoamine oxidases (MAO) in the pathogenesis of heart failure and ischemia/reperfusion injury. , 2011, Biochimica et biophysica acta.

[88]  F. Di Lisa,et al.  Oxidation of myofibrillar proteins in human heart failure. , 2011, Journal of the American College of Cardiology.

[89]  Benedikt Westermann,et al.  Mitochondrial fusion and fission in cell life and death , 2010, Nature Reviews Molecular Cell Biology.

[90]  Marina Bayeva,et al.  Mitochondrial Dysfunction and Oxidative Damage to Sarcomeric Proteins , 2010, Current hypertension reports.

[91]  S. Cortassa,et al.  Redox-optimized ROS balance: a unifying hypothesis. , 2010, Biochimica et biophysica acta.

[92]  J. Rydström,et al.  Diminished NADPH transhydrogenase activity and mitochondrial redox regulation in human failing myocardium. , 2010, Biochimica et biophysica acta.

[93]  G. Schuler,et al.  Impact of high-dose N-acetylcysteine versus placebo on contrast-induced nephropathy and myocardial reperfusion injury in unselected patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. The LIPSIA-N-ACC (Prospective, Single-Blind, Placebo-Con , 2010, Journal of the American College of Cardiology.

[94]  W. Guo,et al.  Hydrogen sulfide attenuates cardiac dysfunction in a rat model of heart failure: a mechanism through cardiac mitochondrial protection , 2010, Bioscience reports.

[95]  W. Paulus,et al.  Antioxidant treatment attenuates pulmonary arterial hypertension-induced heart failure. , 2010, American journal of physiology. Heart and circulatory physiology.

[96]  F. Stillitano,et al.  Enhanced ROS production by NADPH oxidase is correlated to changes in antioxidant enzyme activity in human heart failure. , 2010, Biochimica et biophysica acta.

[97]  T. Gasser,et al.  Analysis of differential DNA damage in the mitochondrial genome employing a semi-long run real-time PCR approach , 2009, Nucleic acids research.

[98]  C. Long,et al.  Chronic Pulmonary Artery Pressure Elevation Is Insufficient to Explain Right Heart Failure , 2009, Circulation.

[99]  Kohtaro Abe,et al.  The right ventricle under pressure: cellular and molecular mechanisms of right-heart failure in pulmonary hypertension. , 2009, Chest.

[100]  Can Ince,et al.  In vivo mitochondrial oxygen tension measured by a delayed fluorescence lifetime technique. , 2008, Biophysical journal.

[101]  J. Dyck,et al.  A dynamic and chamber-specific mitochondrial remodeling in right ventricular hypertrophy can be therapeutically targeted. , 2008, The Journal of thoracic and cardiovascular surgery.

[102]  J. Strahler,et al.  Quantifying changes in the thiol redox proteome upon oxidative stress in vivo , 2008, Proceedings of the National Academy of Sciences.

[103]  M. J. Wagner,et al.  Right-ventricular failure is associated with increased mitochondrial complex II activity and production of reactive oxygen species. , 2007, Cardiovascular research.

[104]  M. J. Faber,et al.  Time dependent changes in cytoplasmic proteins of the right ventricle during prolonged pressure overload. , 2007, Journal of molecular and cellular cardiology.

[105]  M. Sharpley,et al.  Interaction of the Mitochondria-targeted Antioxidant MitoQ with Phospholipid Bilayers and Ubiquinone Oxidoreductases* , 2007, Journal of Biological Chemistry.

[106]  A. Mugelli,et al.  NADPH oxidase-dependent redox signaling in human heart failure: relationship between the left and right ventricle. , 2007, Journal of molecular and cellular cardiology.

[107]  Can Ince,et al.  Mitochondrial PO2 measured by delayed fluorescence of endogenous protoporphyrin IX , 2006, Nature Methods.

[108]  S. Mital,et al.  Failure of Right Ventricular Adaptation in Children With Tetralogy of Fallot , 2006, Circulation.

[109]  F. Ashcroft,et al.  Deletion of Nicotinamide Nucleotide Transhydrogenase , 2006, Diabetes.

[110]  C. Epstein,et al.  Genetic modifiers of the phenotype of mice deficient in mitochondrial superoxide dismutase. , 2006, Human molecular genetics.

[111]  H. M. Cochemé,et al.  Mitochondria-targeted redox probes as tools in the study of oxidative damage and ageing , 2005, Mechanisms of Ageing and Development.

[112]  J. Tune,et al.  Mechanisms of Oxygen Demand/Supply Balance in the Right Ventricle , 2005, Experimental biology and medicine.

[113]  H. Szeto,et al.  Cell-permeable Peptide Antioxidants Targeted to Inner Mitochondrial Membrane inhibit Mitochondrial Swelling, Oxidative Cell Death, and Reperfusion Injury* , 2004, Journal of Biological Chemistry.

[114]  Liang-Jun Yan Analysis of Oxidative Modification of Proteins , 2000, Current protocols in protein science.

[115]  K. Yagi,et al.  Loss of molecular interaction between cytochrome c and cardiolipin due to lipid peroxidation. , 1999, Biochemical and biophysical research communications.

[116]  J. Schaper,et al.  Ultrastructural Morphometric Analysis of Myocardium from Dogs, Rats, Hamsters, Mice, and from Human Hearts , 1985, Circulation research.

[117]  A. A. Armoundas,et al.  Functional Implications of Cardiac Mitochondria Clustering. , 2017, Advances in experimental medicine and biology.

[118]  M. Loebe,et al.  Differential Mitochondrial Function in Remodeled Right and Nonremodeled Left Ventricles in Pulmonary Hypertension. , 2016, Journal of cardiac failure.

[119]  S. Archer,et al.  FOXO1-mediated upregulation of pyruvate dehydrogenase kinase-4 (PDK4) decreases glucose oxidation and impairs right ventricular function in pulmonary hypertension: therapeutic benefits of dichloroacetate , 2012, Journal of Molecular Medicine.

[120]  S. Archer,et al.  Therapeutic inhibition of fatty acid oxidation in right ventricular hypertrophy: exploiting Randle’s cycle , 2011, Journal of Molecular Medicine.

[121]  I. Haber,et al.  The inhibition of pyruvate dehydrogenase kinase improves impaired cardiac function and electrical remodeling in two models of right ventricular hypertrophy: resuscitating the hibernating right ventricle , 2009, Journal of Molecular Medicine.

[122]  Robin A. J. Smith,et al.  Reactivity of ubiquinone and ubiquinol with superoxide and the hydroperoxyl radical: implications for in vivo antioxidant activity. , 2009, Free radical biology & medicine.

[123]  K. Tanonaka,et al.  Possible involvement of mitochondrial energy-producing ability in the development of right ventricular failure in monocrotaline-induced pulmonary hypertensive rats. , 2009, Journal of pharmacological sciences.

[124]  X. Leverve,et al.  Subcellular heterogeneity of mitochondrial function and dysfunction: Evidence obtained by confocal imaging , 2004, Molecular and Cellular Biochemistry.

[125]  N. van Zandwijk N‐Acetylcysteine (NAC) and glutathione (GSH): Antioxidant and chemopreventive properties, with special reference to lung cancer , 1995, Journal of cellular biochemistry. Supplement.