Adrenergic signaling in heart failure and cardiovascular aging.

Both cardiovascular disease and aging are associated with changes in the sympathetic nervous system. Indeed, mounting evidence indicates that adrenergic receptors are functionally involved in numerous processes underlying both aging and cardiovascular disorders, in particular heart failure. This article will review the pathophysiological role of the sympathetic nervous system in heart failure and cardiovascular aging.

[1]  Xiao-Ming Gao,et al.  Spontaneous ventricular tachyarrhythmias in β2-adrenoceptor transgenic mice in relation to cardiac interstitial fibrosis. , 2015, American journal of physiology. Heart and circulatory physiology.

[2]  R. Gainetdinov,et al.  G protein-coupled receptor kinase 5 regulates airway responses induced by muscarinic receptor activation. , 2004, American journal of physiology. Lung cellular and molecular physiology.

[3]  S. Heymans,et al.  Integrating cardiac PIP3 and cAMP signaling through a PKA anchoring function of p110γ. , 2011, Molecular cell.

[4]  C. Stehouwer,et al.  Microvascular Dysfunction: A Potential Mechanism in the Pathogenesis of Obesity‐associated Insulin Resistance and Hypertension , 2012, Microcirculation.

[5]  D. Hardie,et al.  AMPK: a nutrient and energy sensor that maintains energy homeostasis , 2012, Nature Reviews Molecular Cell Biology.

[6]  D. Sorriento,et al.  Integrating GRK2 and NFkappaB in the Pathophysiology of Cardiac Hypertrophy , 2015, Journal of Cardiovascular Translational Research.

[7]  M. Entman,et al.  Mesenchymal stem cell-derived inflammatory fibroblasts mediate interstitial fibrosis in the aging heart. , 2016, Journal of molecular and cellular cardiology.

[8]  M. Ciccarelli,et al.  Adrenergic receptors and metabolism: role in development of cardiovascular disease , 2013, Front. Physiol..

[9]  B. Trimarco,et al.  The Pl(A1/A2) polymorphism of glycoprotein IIIa and cerebrovascular events in hypertension: increased risk of ischemic stroke in high-risk patients. , 2007, Journal of hypertension.

[10]  Henri Xhaard,et al.  Conserved structural, pharmacological and functional properties among the three human and five zebrafish α2‐adrenoceptors , 2005, British journal of pharmacology.

[11]  Zhan Yin,et al.  The regulatory role of the adrenergic agonists phenylephrine and isoproterenol on fetal hemoglobin expression and erythroid differentiation. , 2013, Endocrinology.

[12]  J. Fleg,et al.  Left ventricular remodeling with age in normal men versus women: novel insights using three-dimensional magnetic resonance imaging. , 2002, The American journal of cardiology.

[13]  M. Simon,et al.  Mice Lacking G-Protein Receptor Kinase 1 Have Profoundly Slowed Recovery of Cone-Driven Retinal Responses , 2000, The Journal of Neuroscience.

[14]  A. Baker,et al.  Cardiac Alpha1-Adrenergic Receptors: Novel Aspects of Expression, Signaling Mechanisms, Physiologic Function, and Clinical Importance , 2014, Pharmacological Reviews.

[15]  K. S. Shiny,et al.  Protective effect of taurine on myocardial antioxidant status in isoprenaline‐induced myocardial infarction in rats , 2005, The Journal of pharmacy and pharmacology.

[16]  S. Vatner,et al.  Modulation of β-adrenergic receptor signaling in heart failure and longevity: targeting adenylyl cyclase type 5 , 2010, Heart Failure Reviews.

[17]  M. Chiariello,et al.  Ischemic Neoangiogenesis Enhanced by &bgr;2-Adrenergic Receptor Overexpression: A Novel Role for the Endothelial Adrenergic System , 2005, Circulation research.

[18]  D. Sorriento,et al.  Age-Related Impairment in Insulin Release , 2012, Diabetes.

[19]  H. Kurose,et al.  Multiple functions of G protein-coupled receptor kinases , 2014, Journal of molecular signaling.

[20]  M. Ciccarelli,et al.  Enhanced GRK2 Expression and Desensitization of βAR Vasodilatation in Hypertensive Patients , 2008, Clinical and translational science.

[21]  G. Santulli.  MicroRNAs and Endothelial (Dys) Function , 2016, Journal of cellular physiology.

[22]  I. Marcipar,et al.  β1-selective adrenoceptor antagonists increase plasma levels of anti-p2β antibodies and decrease cardiac involvement in chronic progressive Chagas heart disease. , 2014, The Canadian journal of cardiology.

[23]  M. Illario,et al.  Trafficking GRK2: Cellular and Metabolic consequences of GRK2 subcellular localization. , 2014, Translational medicine @ UniSa.

[24]  K. Sakamoto,et al.  Emerging role for AS 160 / TBC 1 D 4 and TBC 1 D 1 in the regulation of GLUT 4 traffic , 2008 .

[25]  T. Tuschl,et al.  A selective microRNA-based strategy inhibits restenosis while preserving endothelial function. , 2014, The Journal of clinical investigation.

[26]  L. Gepstein,et al.  Effect of aging on the cardiovascular regulatory systems in healthy women. , 2007, American journal of physiology. Regulatory, integrative and comparative physiology.

[27]  Wenjun Xie,et al.  Calcium release channel RyR 2 regulates insulin release and glucose homeostasis , 2019 .

[28]  G. Dorn,et al.  Low- and high-level transgenic expression of β2-adrenergic receptors differentially affect cardiac hypertrophy and function in Gαq-overexpressing mice , 1999 .

[29]  G. Lembo,et al.  Characterization of nitric oxide release by nebivolol and its metabolites. , 2006, American journal of hypertension.

[30]  Connell,et al.  Cardiac Alpha 1-Adrenergic Receptors : Novel Aspects of Expression , Signaling Mechanisms , Physiologic Function , and Clinical Importance , 2013 .

[31]  D. Seals,et al.  Influence of ageing on the sympathetic nervous system and adrenal medulla at rest and during stress , 2004, Biogerontology.

[32]  E. Eugster,et al.  Differential expression of GRK isoforms in nonmalignant and malignant human granulosa cells , 2003, Endocrine.

[33]  Zhonglin Xie,et al.  beta1 integrins expression in adult rat ventricular myocytes and its role in the regulation of beta-adrenergic receptor-stimulated apoptosis. , 2003, Journal of cellular biochemistry.

[34]  A. Zanchetti,et al.  Moderate Leisure Time Physical Activity and Occurrence of Cardiovascular Events: A 10-year Follow-up in the Gubbio Population Study , 2014 .

[35]  Wenjun Xie,et al.  Genetically enhancing mitochondrial antioxidant activity improves muscle function in aging , 2014, Proceedings of the National Academy of Sciences.

[36]  G. Condorelli,et al.  CaMK4 Gene Deletion Induces Hypertension , 2012, Journal of the American Heart Association.

[37]  J. Bijlsma,et al.  Decreased expression and activity of G‐protein‐coupled receptor kinases in peripheral blood mononuclear cells of patients with rheumatoid arthritis , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[38]  G. Santulli,et al.  Development of atrial fibrillation in recipients of cardiac resynchronization therapy: the role of atrial reverse remodelling. , 2012, The Canadian journal of cardiology.

[39]  A. Lymperopoulos,et al.  Regulation of Catecholamine Production from the Adrenal Medulla , 2015 .

[40]  G. Paolisso,et al.  Functional role of miRNA in cardiac resynchronization therapy. , 2014, Pharmacogenomics.

[41]  B. Trimarco,et al.  The PlA1/A2 polymorphism of glycoprotein IIIa and cerebrovascular events in hypertension: increased risk of ischemic stroke in high-risk patients , 2007 .

[42]  Ö. Uğur,et al.  Cell Contact-dependent Functional Selectivity of β2-Adrenergic Receptor Ligands in Stimulating cAMP Accumulation and Extracellular Signal-regulated Kinase Phosphorylation* , 2012, The Journal of Biological Chemistry.

[43]  Xiaodong Cheng,et al.  Critical role for Epac1 in inflammatory pain controlled by GRK2-mediated phosphorylation of Epac1 , 2016, Proceedings of the National Academy of Sciences.

[44]  J. Dixon,et al.  Neuroadrenergic Dysfunction Along the Diabetes Continuum , 2012, Diabetes.

[45]  Gaetano Santulli,et al.  Pinpointing beta adrenergic receptor in ageing pathophysiology: victim or executioner? Evidence from crime scenes , 2013, Immunity & Ageing.

[46]  T. Hussain,et al.  GRK2 Negatively Regulates Glycogen Synthesis in Mouse Liver FL83B Cells* , 2007, Journal of Biological Chemistry.

[47]  Zhonglin Xie,et al.  β1 integrins expression in adult rat ventricular myocytes and its role in the regulation of β‐adrenergic receptor‐stimulated apoptosis , 2003 .

[48]  G. Condorelli,et al.  Atrial fibrillation and microRNAs , 2014, Front. Physiol..

[49]  Gaetano Santulli,et al.  Mitochondrial calcium overload is a key determinant in heart failure , 2015, Proceedings of the National Academy of Sciences.

[50]  J. Port,et al.  Age‐Related Changes in β‐Adrenergic Neuroeffector Systems in the Human Heart , 1994, Circulation.

[51]  A. Bonen,et al.  Membrane fatty acid transporters as regulators of lipid metabolism: implications for metabolic disease. , 2010, Physiological reviews.

[52]  A. Fecher,et al.  Hemodynamic monitoring in the intensive care unit. , 2012, Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition.

[53]  G. Santulli.  microRNAs Distinctively Regulate Vascular Smooth Muscle and Endothelial Cells: Functional Implications in Angiogenesis, Atherosclerosis, and In-Stent Restenosis. , 2015, Advances in experimental medicine and biology.

[54]  M. Caron,et al.  Agonist-Specific Regulation of δ-Opioid Receptor Trafficking by G Protein-Coupled Receptor Kinase and β-Arrestin , 1999 .

[55]  P. Rabinovitch,et al.  Cardiac aging in mice and humans: the role of mitochondrial oxidative stress. , 2009, Trends in cardiovascular medicine.

[56]  Guido Iaccarino,et al.  Overproduction of phosphoprotein enriched in diabetes (PED) induces mesangial expansion and upregulates protein kinase C-β activity and TGF-β1 expression , 2009, Diabetologia.

[57]  G. Dorn,et al.  Mitochondrial localization unveils a novel role for GRK2 in organelle biogenesis. , 2012, Cellular signalling.

[58]  F. Piscione,et al.  Endothelial alpha1-adrenoceptors regulate neo-angiogenesis. , 2008, British journal of pharmacology.

[59]  E. Horton,et al.  Effects of norepinephrine infusion on in vivo insulin sensitivity and responsiveness. , 1990, The American journal of physiology.

[60]  Andrew W. Trafford,et al.  Aging and the cardiac collagen matrix: Novel mediators of fibrotic remodelling , 2016, Journal of molecular and cellular cardiology.

[61]  Chih-Chin Hsu,et al.  Activation of lymphocyte autophagy/apoptosis reflects haemodynamic inefficiency and functional aerobic impairment in patients with heart failure. , 2014, Clinical science.

[62]  R. Cooksey,et al.  Mechanisms for increased myocardial fatty acid utilization following short-term high-fat feeding. , 2009, Cardiovascular research.

[63]  J. Guilhot,et al.  Expression and activity of g protein-coupled receptor kinases in differentiated thyroid carcinoma. , 2002, The Journal of clinical endocrinology and metabolism.

[64]  W. Shen,et al.  Role of PDE3A in regulation of cell cycle progression in mouse vascular smooth muscle cells and oocytes: implications in cardiovascular diseases and infertility. , 2011, Current opinion in pharmacology.

[65]  A. Bruzzone,et al.  Dosage‐dependent regulation of cell proliferation and adhesion through dual β2‐adrenergic receptor/cAMP signals , 2014, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[66]  M. Muller,et al.  β-Adrenergic receptor blockade impairs coronary exercise hyperemia in young men but not older men. , 2014, American journal of physiology. Heart and circulatory physiology.

[67]  S. Paiva,et al.  Energy Metabolism in Cardiac Remodeling and Heart Failure , 2013, Cardiology in review.

[68]  C. DeStephan,et al.  Hemodynamic Monitoring in the Intensive Care Unit , 2014 .

[69]  M. Zile,et al.  Inhibition of collagen cross-linking: effects on fibrillar collagen and ventricular diastolic function. , 1995, The American journal of physiology.

[70]  Christopher J. Lyon,et al.  Insulin resistance and the endothelium , 2005, The American journal of medicine.

[71]  L. Philipson.  beta-Agonists and metabolism. , 2002, The Journal of allergy and clinical immunology.

[72]  D. Sorriento,et al.  Endothelial Cells Are Able to Synthesize and Release Catecholamines Both In Vitro and In Vivo , 2012, Hypertension.

[73]  J. Kros,et al.  β-Arrestin 1 and 2 and G protein-coupled receptor kinase 2 expression in pituitary adenomas: role in the regulation of response to somatostatin analogue treatment in patients with acromegaly. , 2013, Endocrinology.

[74]  C. Kahn,et al.  Excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload in rodents. , 2010, The Journal of clinical investigation.

[75]  J. Mariani,et al.  Sympathetic Neural Adaptation to Hypocaloric Diet With or Without Exercise Training in Obese Metabolic Syndrome Subjects , 2009, Diabetes.

[76]  G. Santulli.  Adrenal signaling in heart failure: something more than a distant ship's smoke on the horizon. , 2014, Hypertension.

[77]  Guangju Ji,et al.  Functional Role of Calstabin2 in Age-related Cardiac Alterations , 2014, Scientific Reports.

[78]  D. Sorriento,et al.  Intracardiac Injection of AdGRK5-NT Reduces Left Ventricular Hypertrophy by Inhibiting NF-&kgr;B–Dependent Hypertrophic Gene Expression , 2010, Hypertension.

[79]  J. Benovic,et al.  G-Protein-coupled receptor kinase activity in hypertension : increased vascular and lymphocyte G-protein receptor kinase-2 protein expression. , 2000, Hypertension.

[80]  M. Esler,et al.  Sympathetic neuronal regulation of the heart in aging and heart failure. , 2005, Cardiovascular research.

[81]  I. Poornima,et al.  The effects of combined versus selective adrenergic blockade on left ventricular and systemic hemodynamics, myocardial substrate preference, and regional perfusion in conscious dogs with dilated cardiomyopathy. , 2006, Journal of the American College of Cardiology.

[82]  G. Santulli.  The Adrenergic System in Cardiovascular Metabolism and Aging , 2015 .

[83]  F. Veglia,et al.  Neurohormonal activation is associated with increased levels of plasma matrix metalloproteinase-2 in human heart failure. , 2005, European heart journal.

[84]  Thomas O'Hara,et al.  Caveolin-3 regulates compartmentation of cardiomyocyte beta2-adrenergic receptor-mediated cAMP signaling. , 2014, Journal of molecular and cellular cardiology.

[85]  G. Jennings,et al.  Age-dependent cardiomyopathy and heart failure phenotype in mice overexpressing beta(2)-adrenergic receptors in the heart. , 2000, Cardiovascular research.

[86]  D. Parikh,et al.  Insulin Inhibits Cardiac Contractility by Inducing a Gi-Biased β2-Adrenergic Signaling in Hearts , 2014, Diabetes.

[87]  P. Vardas,et al.  Healthy aging and myocardium: A complicated process with various effects in cardiac structure and physiology. , 2016, International journal of cardiology.

[88]  R. Xiao.  β-Adrenergic Signaling in the Heart: Dual Coupling of the β2-Adrenergic Receptor to Gs and Gi Proteins , 2001, Science's STKE.

[89]  G. Dorn,et al.  Low- and high-level transgenic expression of beta2-adrenergic receptors differentially affect cardiac hypertrophy and function in Galphaq-overexpressing mice. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[90]  W. Koch,et al.  Impaired neoangiogenesis in β2–adrenoceptor gene‐deficient mice: restoration by intravascular human β2–adrenoceptor gene transfer and role of NFκB and CREB transcription factors , 2011, British journal of pharmacology.

[91]  R. Marfella,et al.  Impact of Diabetes Mellitus on the Clinical Response to Cardiac Resynchronization Therapy in Elderly People , 2014, Journal of Cardiovascular Translational Research.

[92]  G. Schernthaner.  Pleiotropic effects of thiazolidinediones on traditional and non‐traditional atherosclerotic risk factors , 2009, International journal of clinical practice.

[93]  C. Murga,et al.  Increased Nitric Oxide Bioavailability in Adult GRK2 Hemizygous Mice Protects Against Angiotensin II–Induced Hypertension , 2014, Hypertension.

[94]  G. Santulli.  Coronary heart disease risk factors and mortality. , 2012, JAMA.

[95]  M. Caron,et al.  G Protein-Coupled Receptor Kinase 2 in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis , 2005, The Journal of Immunology.

[96]  C. Murga,et al.  Increased Nitric Oxide Bioavailability in Adult GRK 2 Hemizygous Mice Protects Against Angiotensin II – Induced Hypertension , 2022 .

[97]  D. Sorriento,et al.  Evaluation of the anti-angiogenic properties of the new selective αVβ3 integrin antagonist RGDechiHCit , 2011, Journal of Translational Medicine.

[98]  Y. Kihara,et al.  Excessive activation of matrix metalloproteinases coincides with left ventricular remodeling during transition from hypertrophy to heart failure in hypertensive rats. , 2002, Journal of the American College of Cardiology.

[99]  K. Sakamoto,et al.  Emerging role for AS160/TBC1D4 and TBC1D1 in the regulation of GLUT4 traffic. , 2008, American journal of physiology. Endocrinology and metabolism.

[100]  J. Atkinson,et al.  Aminoguanidine and Aortic Wall Mechanics, Structure, and Composition in Aged Rats , 2001, Hypertension.

[101]  J. Dixon,et al.  393 NEUROADRENERGIC DYSFUNCTION ALONG THE DIABETIC CONTINUUM: A COMPARATIVE STUDY IN OBESE METABOLIC SYNDROME SUBJECTS , 2012 .

[102]  M. Lohse,et al.  Progressive hypertrophy and heart failure in beta1-adrenergic receptor transgenic mice. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[103]  M. Cawthorne,et al.  Metabolic responses to BRL37344 and clenbuterol in soleus muscle and C2C12 cells via different atypical pharmacologies and β2‐adrenoceptor mechanisms , 2008, British journal of pharmacology.

[104]  J. Balligand,et al.  Enhanced Expression of Β3-adrenoceptors in Cardiac Myocytes Attenuates Neurohormone-induced Hypertrophic Remodeling through Nitric Oxide Synthase Heart Failure Neurohormonal Stimulation , 2022 .

[105]  M. Ciccarelli,et al.  Physical activity ameliorates cardiovascular health in elderly subjects: the functional role of the β adrenergic system , 2013, Front. Physiol..

[106]  W. Koch,et al.  Myocardial Gene Transfer and Overexpression of &bgr;2-Adrenergic Receptors Potentiates the Functional Recovery of Unloaded Failing Hearts , 2002, Circulation.

[107]  G. Lembo,et al.  Nitric oxide mechanisms of nebivolol , 2009, Therapeutic advances in cardiovascular disease.

[108]  Longjian Liu,et al.  Systematic Review and Meta-Analysis Evaluating the Impact of Vitamin D on the Risk of Heart Failure: New Evidence from Population-based Studies , 2014 .

[109]  P. Kellman,et al.  Myocardial Fibrosis Quantified by Extracellular Volume Is Associated With Subsequent Hospitalization for Heart Failure, Death, or Both Across the Spectrum of Ejection Fraction and Heart Failure Stage , 2015, Journal of the American Heart Association.

[110]  A. Slusher,et al.  Acute aerobic exercise mediates G protein-coupled receptor kinase 2 expression in human PBMCs. , 2015, Life sciences.

[111]  K. Baar,et al.  Regulation of contractility and metabolic signaling by the β2-adrenergic receptor in rat ventricular muscle. , 2011, Life sciences.

[112]  L. Philipson.  β-Agonists and metabolism , 2002 .

[113]  D. Babuty,et al.  β-Adrenergic blockade combined with subcutaneous B-type natriuretic peptide: a promising approach to reduce ventricular arrhythmia in heart failure? , 2014, Heart.

[114]  D. Lloyd‐Jones,et al.  Prospective Relationship of Low Cardiovascular Risk Factor Profile at Younger Ages to Ankle-Brachial Index: 39-Year Follow-Up—The Chicago Healthy Aging Study , 2012, Journal of the American Heart Association.

[115]  Wenjun Xie,et al.  Mitochondrial oxidative stress promotes atrial fibrillation , 2015, Scientific Reports.

[116]  M. Caron,et al.  Agonist-specific regulation of delta-opioid receptor trafficking by G protein-coupled receptor kinase and beta-arrestin. , 1999, Journal of receptor and signal transduction research.

[117]  G. Condorelli,et al.  The possible role of chromosome X variability in hypertensive familiarity , 2016, Journal of Human Hypertension.

[118]  Gaetano Santulli,et al.  Imaging atrial arrhythmic intracellular calcium in intact heart. , 2013, Journal of molecular and cellular cardiology.

[119]  B. Citron,et al.  Abnormality of G-Protein-Coupled Receptor Kinases at Prodromal and Early Stages of Alzheimer's Disease: An Association with Early β-Amyloid Accumulation , 2004, The Journal of Neuroscience.

[120]  J. Pittet,et al.  IL‐8 inhibits cAMP‐stimulated alveolar epithelial fluid transport via a GRK2/PI3K‐dependent mechanism , 2013, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[121]  M. Scheinin,et al.  Inhibition of α-adrenergic tone disturbs the distribution of blood flow in the exercising human limb. , 2013, American journal of physiology. Heart and circulatory physiology.

[122]  Gaetano Santulli,et al.  Epidemiology of cardiovascular disease in the 21st century: Updated updated numbers and updated facts , 2013 .

[123]  E. Richter,et al.  Current understanding of increased insulin sensitivity after exercise – emerging candidates , 2011, Acta physiologica.

[124]  G. Condorelli,et al.  AKT Participates in Endothelial Dysfunction in Hypertension , 2004, Circulation.

[125]  W. Tseng,et al.  Myocardial Regional Interstitial Fibrosis is Associated With Left Intra-Ventricular Dyssynchrony in Patients With Heart Failure: A Cardiovascular Magnetic Resonance Study , 2016, Scientific Reports.

[126]  D. Leosco,et al.  The G protein coupled receptor kinase 2 plays an essential role in beta-adrenergic receptor-induced insulin resistance. , 2009, Cardiovascular research.

[127]  Marc G Caron,et al.  Dopaminergic Supersensitivity in G Protein-Coupled Receptor Kinase 6-Deficient Mice , 2003, Neuron.

[128]  F. Piscione,et al.  Endothelial α1‐adrenoceptors regulate neo‐angiogenesis , 2008 .

[129]  R. Freeman,et al.  Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management , 2011, Diabetes/metabolism research and reviews.

[130]  W. Paulus,et al.  Cellular mechanisms for diastolic dysfunction in the human heart. , 2012, Current pharmaceutical biotechnology.

[131]  W. Koch,et al.  Prodeath Signaling of G Protein–Coupled Receptor Kinase 2 in Cardiac Myocytes After Ischemic Stress Occurs Via Extracellular Signal–Regulated Kinase-Dependent Heat Shock Protein 90–Mediated Mitochondrial Targeting , 2013, Circulation research.

[132]  Edmund O. Acevedo,et al.  Cardiovascular reactivity, stress, and physical activity , 2013, Front. Physiol..

[133]  A. Marks,et al.  Essential Roles of Intracellular Calcium Release Channels in Muscle, Brain, Metabolism, and Aging. , 2015, Current molecular pharmacology.

[134]  M. Chiariello,et al.  Cardiac resynchronisation therapy response predicts occurrence of atrial fibrillation in non‐ischaemic dilated cardiomyopathy , 2011, International journal of clinical practice.

[135]  M. Ciccarelli,et al.  G protein-coupled receptor kinase 2 in patients with acute myocardial infarction. , 2011, The American journal of cardiology.

[136]  J. Hawley,et al.  Low intrinsic exercise capacity in rats predisposes to age-dependent cardiac remodeling independent of macrovascular function. , 2013, American journal of physiology. Heart and circulatory physiology.

[137]  I. Page,et al.  Cardiovascular Reactivity , 1954, Circulation research.

[138]  D. Kass,et al.  Cardiac resynchronization sensitizes the sarcomere to calcium by reactivating GSK-3β. , 2014, The Journal of clinical investigation.