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Hypothalamic dysfunction in heart failure: pathogenetic mechanisms and therapeutic implications

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Abstract

Neurohumoral activation is an important feature of heart failure. Recent advances in molecular biology and imaging techniques permitted a better understanding of the central role that hypothalamus plays in the modulation of dysfunctional mechanisms, as well as the occurrence of comorbidities, such as depression, in heart failure patients. This review summarizes the commonly reported neural reflexes and molecular signaling pathways at the level of the hypothalamus along with the dysfunctional mechanisms within the paraventricular nucleus and other areas of the hypothalamus in heart failure and describes some relevant therapeutic implications.

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References

  1. Sousa-Pinto B, Ferreira-Pinto MJ, Santos M, Leite-Moreira AF (2014) Central nervous system circuits modified in heart failure: pathophysiology and therapeutic implications. Heart Fail Rev 19:759–779

    Article  CAS  PubMed  Google Scholar 

  2. Sam S, Frohman LA (2008) Normal physiology of hypothalamic pituitary regulation. Endocrinol Metab Clin N Am 37:1–22 vii

    Article  CAS  Google Scholar 

  3. Felder RB, Francis J, Zhang ZH, Wei SG, Weiss RM, Johnson AK (2003) Heart failure and the brain: new perspectives. Am J Physiol Regul Integr Comp Physiol 284:R259–R276

    Article  CAS  PubMed  Google Scholar 

  4. Pyner S (2014) The paraventricular nucleus and heart failure. Exp Physiol 99:332–339

    Article  CAS  PubMed  Google Scholar 

  5. Dampney RA, Horiuchi J, Killinger S, Sheriff MJ, Tan PS, McDowall LM (2005) Long-term regulation of arterial blood pressure by hypothalamic nuclei: some critical questions. Clin Exp Pharmacol Physiol 32:419–425

    Article  CAS  PubMed  Google Scholar 

  6. Triposkiadis F, Karayannis G, Giamouzis G, Skoularigis J, Louridas G, Butler J (2009) The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications. J Am Coll Cardiol 54:1747–1762

    Article  CAS  PubMed  Google Scholar 

  7. Zucker IH, Patel KP, Schultz HD (2012) Neurohumoral stimulation. Heart Fail Clin 8:87–99

    Article  PubMed  PubMed Central  Google Scholar 

  8. Parissis JT, Farmakis D, Nikolaou M, Birmpa D, Bistola V, Paraskevaidis I, Ikonomidis I, Gaitani S, Venetsanou K, Filippatos G, Kremastinos DT (2009) Plasma B-type natriuretic peptide and anti-inflammatory cytokine interleukin-10 levels predict adverse clinical outcome in chronic heart failure patients with depressive symptoms: a 1-year follow-up study. Eur J Heart Fail 11:967–972

    Article  CAS  PubMed  Google Scholar 

  9. Parissis JT, Adamopoulos S, Rigas A, Kostakis G, Karatzas D, Venetsanou K, Kremastinos DT (2004) Comparison of circulating proinflammatory cytokines and soluble apoptosis mediators in patients with chronic heart failure with versus without symptoms of depression. Am J Cardiol 94:1326–1328

    Article  CAS  PubMed  Google Scholar 

  10. Ito K, Hirooka Y, Sunagawa K (2015) Cardiac sympathetic afferent stimulation induces salt-sensitive sympathoexcitation through hypothalamic epithelial Na+ channel activation. Am J Physiol Heart Circ Physiol 308:H530–H539

    Article  CAS  PubMed  Google Scholar 

  11. Huang BS, Zheng H, Tan J, Patel KP, Leenen FH (2011) Regulation of hypothalamic renin-angiotensin system and oxidative stress by aldosterone. Exp Physiol 96:1028–1038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wang W, McClain JM, Zucker IH (1992) Aldosterone reduces baroreceptor discharge in the dog. Hypertension 19:270–277

    Article  CAS  PubMed  Google Scholar 

  13. Li YL, Xia XH, Zheng H, Gao L, Li YF, Liu D, Patel KP, Wang W, Schultz HD (2006) Angiotensin II enhances carotid body chemoreflex control of sympathetic outflow in chronic heart failure rabbits. Cardiovasc Res 71:129–138

    Article  CAS  PubMed  Google Scholar 

  14. Sharma NM, Zheng H, Li YF, Patel KP (2012) Nitric oxide inhibits the expression of AT1 receptors in neurons. Am J Phys Cell Phys 302:C1162–C1173

    Article  CAS  Google Scholar 

  15. Gao L, Wang W, Li YL, Schultz HD, Liu D, Cornish KG, Zucker IH (2004) Superoxide mediates sympathoexcitation in heart failure: roles of angiotensin II and NAD(P)H oxidase. Circ Res 95:937–944

    Article  CAS  PubMed  Google Scholar 

  16. Chen Q, Pan HL (2007) Signaling mechanisms of angiotensin II-induced attenuation of GABAergic input to hypothalamic presympathetic neurons. J Neurophysiol 97:3279–3287

    Article  CAS  PubMed  Google Scholar 

  17. Yu Y, Wei SG, Zhang ZH, Gomez-Sanchez E, Weiss RM, Felder RB (2008) Does aldosterone upregulate the brain renin-angiotensin system in rats with heart failure? Hypertension 51:727–733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Xue B, Beltz TG, Yu Y, Guo F, Gomez-Sanchez CE, Hay M, Johnson AK (2011) Central interactions of aldosterone and angiotensin II in aldosterone- and angiotensin II-induced hypertension. Am J Physiol Heart Circ Physiol 300:H555–H564

    Article  CAS  PubMed  Google Scholar 

  19. Isgaard J, Granata R (2011) Ghrelin in cardiovascular disease and atherogenesis. Mol Cell Endocrinol 340:59–64

    Article  CAS  PubMed  Google Scholar 

  20. Japp AG, Newby DE (2008) The apelin-APJ system in heart failure: pathophysiologic relevance and therapeutic potential. Biochem Pharmacol 75:1882–1892

    Article  CAS  PubMed  Google Scholar 

  21. Angelova PR, Kasymov V, Christie I, Sheikhbahaei S, Turovsky E, Marina N, Korsak A, Zwicker J, Teschemacher AG, Ackland GL, Funk GD, Kasparov S, Abramov AY, Gourine AV (2015) Functional oxygen sensitivity of astrocytes. J Neurosci 35:10460–10473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Parissis JT, Fountoulaki K, Paraskevaidis I, Kremastinos D (2005) Depression in chronic heart failure: novel pathophysiological mechanisms and therapeutic approaches. Expert Opin Investig Drugs 14:567–577

    Article  CAS  PubMed  Google Scholar 

  23. Halaris A (2013) Inflammation, heart disease, and depression. Curr Psychiatry Rep 15:400

    Article  PubMed  Google Scholar 

  24. Parissis JT, Fountoulaki K, Filippatos G, Adamopoulos S, Paraskevaidis I, Kremastinos D (2007) Depression in coronary artery disease: novel pathophysiologic mechanisms and therapeutic implications. Int J Cardiol 116:153–160

    Article  PubMed  Google Scholar 

  25. Parissis JT, Nikolaou M, Farmakis D, Paraskevaidis IA, Bistola V, Venetsanou K, Katsaras D, Filippatos G, Kremastinos DT (2009) Self-assessment of health status is associated with inflammatory activation and predicts long-term outcomes in chronic heart failure. Eur J Heart Fail 11:163–169

    Article  PubMed  PubMed Central  Google Scholar 

  26. Szczepanska-Sadowska E, Cudnoch-Jedrzejewska A, Ufnal M, Zera T (2010) Brain and cardiovascular diseases: common neurogenic background of cardiovascular, metabolic and inflammatory diseases. J Physiol Pharmacol 61:509–521

    CAS  PubMed  Google Scholar 

  27. Wsol A, Cudnoch-Je drzejewska A, Szczepanska-Sadowska E, Kowalewski S, Dobruch J (2009) Central oxytocin modulation of acute stress-induced cardiovascular responses after myocardial infarction in the rat. Stress 12:517–525

    Article  CAS  PubMed  Google Scholar 

  28. Gouweleeuw L, Hovens IB, Liu H, Naude PJ, Schoemaker RG (2016) Differences in the association between behavior and neutrophil gelatinase-associated lipocalin in male and female rats after coronary artery ligation. Physiol Behav 163:7–16

    Article  CAS  PubMed  Google Scholar 

  29. Sole MJ, Benedict CR, Versteeg DH, de Kloet ER (1985) Digitoxin therapy partially restores cardiac catecholamine and brain serotonin metabolism in congestive heart failure. J Mol Cell Cardiol 17:1055–1063

    Article  CAS  PubMed  Google Scholar 

  30. O'Connor CM, Jiang W, Kuchibhatla M, Silva SG, Cuffe MS, Callwood DD, Zakhary B, Stough WG, Arias RM, Rivelli SK, Krishnan R, Investigators S-C (2010) Safety and efficacy of sertraline for depression in patients with heart failure: results of the SADHART-CHF (Sertraline Against Depression and Heart Disease in Chronic Heart Failure) trial. J Am Coll Cardiol 56:692–699

    Article  PubMed  PubMed Central  Google Scholar 

  31. Gottlieb SS, Kop WJ, Thomas SA, Katzen S, Vesely MR, Greenberg N, Marshall J, Cines M, Minshall S (2007) A double-blind placebo-controlled pilot study of controlled-release paroxetine on depression and quality of life in chronic heart failure. Am Heart J 153:868–873

    Article  CAS  PubMed  Google Scholar 

  32. Lekakis J, Ikonomidis I, Papoutsi Z, Moutsatsou P, Nikolaou M, Parissis J, Kremastinos DT (2010) Selective serotonin re-uptake inhibitors decrease the cytokine-induced endothelial adhesion molecule expression, the endothelial adhesiveness to monocytes and the circulating levels of vascular adhesion molecules. Int J Cardiol 139:150–158

    Article  PubMed  Google Scholar 

  33. Fraguas R, da Silva Telles RM, Alves TC, Andrei AM, Rays J, Iosifescu DV, Wajngarten M (2009) A double-blind, placebo-controlled treatment trial of citalopram for major depressive disorder in older patients with heart failure: the relevance of the placebo effect and psychological symptoms. Contemp Clin Trials 30:205–211

    Article  CAS  PubMed  Google Scholar 

  34. Woltz PC, Chapa DW, Friedmann E, Son H, Akintade B, Thomas SA (2012) Effects of interventions on depression in heart failure: a systematic review. Heart Lung 41:469–483

    Article  PubMed  Google Scholar 

  35. Michalakeas CA, Parissis JT, Douzenis A, Nikolaou M, Varounis C, Andreadou I, Antonellos N, Markantonis-Kiroudis S, Paraskevaidis I, Ikonomidis I, Lykouras E, Kremastinos D (2011) Effects of sertraline on circulating markers of oxidative stress in depressed patients with chronic heart failure: a pilot study. J Card Fail 17:748–754

    Article  CAS  PubMed  Google Scholar 

  36. Carney RM, Freedland KE, Stein PK, Skala JA, Hoffman P, Jaffe AS (2000) Change in heart rate and heart rate variability during treatment for depression in patients with coronary heart disease. Psychosom Med 62:639–647

    Article  CAS  PubMed  Google Scholar 

  37. Pereira VH, Cerqueira JJ, Palha JA, Sousa N (2013) Stressed brain, diseased heart: a review on the pathophysiologic mechanisms of neurocardiology. Int J Cardiol 166:30–37

    Article  PubMed  Google Scholar 

  38. Parissis JT, Farmakis D, Fountoulaki K, Rigas A, Nikolaou M, Paraskevaidis IA, Bistola V, Venetsanou K, Ikonomidis I, Anastasiou-Nana M, Kremastinos DT, Filippatos G (2013) Clinical and neurohormonal correlates and prognostic value of serum prolactin levels in patients with chronic heart failure. Eur J Heart Fail 15:1122–1130

    Article  CAS  PubMed  Google Scholar 

  39. Kadoglou NP, Mandila C, Karavidas A, Farmakis D, Matzaraki V, Varounis C, Arapi S, Perpinia A, Parissis J (2017) Effect of functional electrical stimulation on cardiovascular outcomes in patients with chronic heart failure. Eur J Prev Cardiol 24:833–839

  40. Adamopoulos S, Parissis JT, Kremastinos DT (2003) New aspects for the role of physical training in the management of patients with chronic heart failure. Int J Cardiol 90:1–14

    Article  PubMed  Google Scholar 

  41. Korkmaz ME, Muderrisoglu H, Ulucam M, Ozin B (2000) Effects of spironolactone on heart rate variability and left ventricular systolic function in severe ischemic heart failure. Am J Cardiol 86:649–653

    Article  CAS  PubMed  Google Scholar 

  42. Deftereos SN, Dodou E, Andronis C, Persidis A (2012) From depression to neurodegeneration and heart failure: re-examining the potential of MAO inhibitors. Expert Rev Clin Pharmacol 5:413–425

    Article  CAS  PubMed  Google Scholar 

  43. Mochel JP, Fink M, Bon C, Peyrou M, Bieth B, Desevaux C, Deurinck M, Giraudel JM, Danhof M (2014) Influence of feeding schedules on the chronobiology of renin activity, urinary electrolytes and blood pressure in dogs. Chronobiol Int 31:715–730

    Article  CAS  PubMed  Google Scholar 

  44. Basu S, Sinha SK, Shao Q, Ganguly PK, Dhalla NS (1996) Neuropeptide Y modulation of sympathetic activity in myocardial infarction. J Am Coll Cardiol 27:1796–1803

    Article  CAS  PubMed  Google Scholar 

  45. Shi Z, Cassaglia PA, Gotthardt LC, Brooks VL (2015) Hypothalamic paraventricular and arcuate nuclei contribute to elevated sympathetic nerve activity in pregnant rats: roles of neuropeptide Y and alpha-melanocyte-stimulating hormone. Hypertension 66:1191–1198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kanashiro-Takeuchi RM, Szalontay L, Schally AV, Takeuchi LM, Popovics P, Jaszberenyi M, Vidaurre I, Zarandi M, Cai RZ, Block NL, Hare JM, Rick FG (2015) New therapeutic approach to heart failure due to myocardial infarction based on targeting growth hormone-releasing hormone receptor. Oncotarget 6:9728–9739

    Article  PubMed  PubMed Central  Google Scholar 

  47. Bernstein HG, Klix M, Dobrowolny H, Brisch R, Steiner J, Bielau H, Gos T, Bogerts B (2012) A postmortem assessment of mammillary body volume, neuronal number and densities, and fornix volume in subjects with mood disorders. Eur Arch Psychiatry Clin Neurosci 262:637–646

    Article  PubMed  Google Scholar 

  48. Guyenet PG (2014) Regulation of breathing and autonomic outflows by chemoreceptors. Compr Physiol 4:1511–1562

    Article  PubMed  PubMed Central  Google Scholar 

  49. Hayward LF, Hampton EE, Ferreira LF, Christou DD, Yoo JK, Hernandez ME, Martin EJ (2015) Chronic heart failure alters orexin and melanin concentrating hormone but not corticotrophin releasing hormone-related gene expression in the brain of male Lewis rats. Neuropeptides 52:67–72

    Article  CAS  PubMed  Google Scholar 

  50. Perez MV, Pavlovic A, Shang C, Wheeler MT, Miller CL, Liu J, Dewey FE, Pan S, Thanaporn PK, Absher D, Brandimarto J, Salisbury H, Chan K, Mukherjee R, Konadhode RP, Myers RM, Sedehi D, Scammell TE, Quertermous T, Cappola T, Ashley EA (2015) Systems genomics identifies a key role for hypocretin/orexin receptor-2 in human heart failure. J Am Coll Cardiol 66:2522–2533

    Article  CAS  PubMed  Google Scholar 

  51. Wang JM, Tan J, Leenen FH (2003) Central nervous system blockade by peripheral administration of AT1 receptor blockers. J Cardiovasc Pharmacol 41:593–599

    Article  CAS  PubMed  Google Scholar 

  52. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P, Authors/Task Force M, Document R (2016) 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 18:891–975

    Article  PubMed  Google Scholar 

  53. Champion S, Lapidus N, Cherie G, Spagnoli V, Oliary J, Solal AC (2014) Pentoxifylline in heart failure: a meta-analysis of clinical trials. Cardiovasc Ther 32:159–162

    Article  CAS  PubMed  Google Scholar 

  54. Wei SG, Yu Y, Weiss RM, Felder RB (2016) Inhibition of brain mitogen-activated protein kinase signaling reduces central endoplasmic reticulum stress and inflammation and sympathetic nerve activity in heart failure rats. Hypertension 67:229–236

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Heart Failure Unit, Department of Cardiology, Athens University Hospital “Attikon”, National and Kapodistrian University of Athens, Athens, Greece

    Antonios Rigas, Dimitrios Farmakis, Georgios Papingiotis, Georgios Bakosis & John Parissis

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  1. Antonios Rigas
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  2. Dimitrios Farmakis
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  3. Georgios Papingiotis
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  4. Georgios Bakosis
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Correspondence to Dimitrios Farmakis.

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Rigas, A., Farmakis, D., Papingiotis, G. et al. Hypothalamic dysfunction in heart failure: pathogenetic mechanisms and therapeutic implications. Heart Fail Rev 23, 55–61 (2018). https://doi.org/10.1007/s10741-017-9659-7

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