Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Causes and treatment of oedema in patients with heart failure

Nature Reviews Cardiology volume 10, pages 156–170 (2013)Cite this article

Subjects

Abstract

Oedema is one of the fundamental features of heart failure, but the pathophysiology of oedema varies. Patients present along a spectrum ranging from acute pulmonary oedema to gross fluid retention and peripheral oedema (anasarca). In patients with pure pulmonary oedema, the problem is one of acute haemodynamic derangement; the patient does not have excess fluid, but pulmonary venous pressure rises such that the rate of fluid transudation into the interstitium of the lung exceeds the capacity of the pulmonary lymphatics to drain away the fluid. Conversely, in patients with peripheral oedema, the problem is one of fluid retention. Understanding the causes of oedema will enable straightforward, correct management of the condition. For patients with acute pulmonary oedema, vasodilatation is important to reduce cardiac filling pressures. For patients with fluid retention, removing the fluid, using either diuretics or mechanical means, is the most important consideration.

Key Points

  • Oedema is one of the fundamental features of heart failure

  • Clinical trial data to guide best practice in managing cardiac oedema are lacking

  • Acute pulmonary oedema is characterized by accumulation of fluid in the air spaces, not by fluid overload

  • Acute pulmonary oedema is best treated as a haemodynamic problem using vasodilators

  • Peripheral oedema is characterized by an excess of total body water

  • Peripheral oedema is best treated by removing fluid, either with diuretics or mechanically

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The Frank–Starling law of the heart.
Figure 2: The correlation between increasing left atrial pressure and the rate of development of pulmonary oedema.
Figure 3: X-ray of the chest of a patient presenting with acute pulmonary oedema.
Figure 4: Schematic representation of possible routes through which vasodilators exert their action.
Figure 5: The right thigh of a patient presenting with fluid retention and pitting oedema.
Figure 6: Pattern of weight loss in a patient presenting with peripheral oedema.
Figure 7: Time course of serum sodium level changes in a patient presenting with oedematous heart failure.

Similar content being viewed by others

References

  1. Hospital Episode Statistics. HES online [online], (2012).

  2. Cleland, J. G. et al. The national heart failure audit for England and Wales 2008–2009 Heart 97, 876–86 (2011).

    Article  PubMed  Google Scholar 

  3. National Heart Failure Audit 2010. The NHS Information Centre [online], (2012).

  4. Michalsen, A., König, G. & Thimme, W. Preventable causative factors leading to hospital admission with decompensated heart failure. Heart 80, 437–441 (1998).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Fonarow, G. C. et al. Factors identified as precipitating hospital admissions for heart failure and clinical outcomes: findings from OPTIMIZE-HF. Arch. Intern. Med. 168, 847–854 (2008).

    Article  PubMed  Google Scholar 

  6. Roguin, A. et al. Long-term prognosis of acute pulmonary oedema--an ominous outcome. Eur. J. Heart Fail. 2, 137–144 (2000).

    Article  CAS  PubMed  Google Scholar 

  7. Starling, E. H. On the absorption of fluids from the connective tissue spaces. J. Physiol. 19, 312–326 (1896).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Erdmann, A. J. 3rd, Vaughan, T. R. Jr, Brigham, K. L., Woolverton, W. C. & Staub, N. C. Effect of increased vascular pressure on lung fluid balance in unanesthetized sheep. Circ. Res. 37, 271–284 (1975).

    Article  PubMed  Google Scholar 

  9. Guyton, A. C. & Lindsey, A. W. Effect of elevated left atrial pressure and decreased plasma protein concentration on the development of pulmonary edema. Circ. Res. 7, 649–657 (1959).

    Article  CAS  PubMed  Google Scholar 

  10. Figueras, J. & Weil, M. H. Blood volume prior to and following treatment of acute cardiogenic pulmonary edema. Circulation 57, 349–355 (1978).

    Article  CAS  PubMed  Google Scholar 

  11. Cotter, G. et al. The role of cardiac power and systemic vascular resistance in the pathophysiology and diagnosis of patients with acute congestive heart failure. Eur. J. Heart Fail. 5, 443–451 (2003).

    Article  PubMed  Google Scholar 

  12. Pickering, T. G. et al. Recurrent pulmonary oedema in hypertension due to bilateral renal artery stenosis: treatment by angioplasty or surgical revascularisation. Lancet 2, 551–552 (1988).

    Article  CAS  PubMed  Google Scholar 

  13. Lohmeier, T. E., Mizelle, H. L., Reinhart, G. A. & Montani, J. P. Influence of angiotensin on the early progression of heart failure. Am. J. Physiol. Regul. Integr. Comp. Physiol. 278, R74–R86 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. Hall, J. E. et al. Mechanisms of escape from sodium retention during angiotensin II hypertension. Am. J. Physiol. 246, F627–F634 (1984).

    CAS  PubMed  Google Scholar 

  15. van Iperen, C. E., Giezen, J., Kramer, W. L. M., Lips, C. J. M. & Bartelink, A. K. Acute dyspnea resulting from pulmonary oedema as the first sign of a pheochromocytoma. Respiration 68, 323–326 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Sartori, C., Allemann, Y. & Scherrer, U. Pathogenesis of pulmonary edema: learning from high-altitude pulmonary edema. Respir. Physiol. Neurobiol. 159, 338–349 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Fein, A. et al. The value of edema fluid protein measurements in patients with pulmonary edema. Am. J. Med. 67, 32–38 (1979).

    Article  CAS  PubMed  Google Scholar 

  18. Colombo, P. C., Onat, D. & Sabbah, H. N. Acute heart failure as “acute endothelitis”--Interaction of fluid overload and endothelial dysfunction. Eur. J. Heart Fail. 10, 170–175 (2008).

    Article  PubMed  Google Scholar 

  19. Oldenburg, O. et al. Sleep-disordered breathing in patients with symptomatic heart failure: a contemporary study of prevalence in and characteristics of 700 patients. Eur. J. Heart Fail. 9, 251–257 (2007).

    Article  PubMed  Google Scholar 

  20. Fletcher, E. C. et al. Pulmonary edema develops after recurrent obstructive apneas. Am. J. Respir. Crit. Care Med. 160, 1688–1696 (1999).

    Article  CAS  PubMed  Google Scholar 

  21. Kasai, T. et al. Relationship between sodium intake and sleep apnea in patients with heart failure. J. Am. Coll. Cardiol. 58, 1970–1974 (2011).

    Article  CAS  PubMed  Google Scholar 

  22. Mackersie, R. C., Christensen, J. & Lewis, F. R. The role of pulmonary lymphatics in the clearance of hydrostatic pulmonary edema. J. Surg. Res. 43, 495–504 (1987).

    Article  CAS  PubMed  Google Scholar 

  23. Tandon, H. D. & Kasturi, J. Pulmonary vascular changes associated with isolated mitral stenosis in India. Br. Heart J. 37, 26–36 (1975).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Davies, S. W. et al. Reduced pulmonary microvascular permeability in severe chronic left heart failure. Am. Heart J. 124, 137–142 (1992).

    Article  CAS  PubMed  Google Scholar 

  25. Huang, W. et al. Capillary filtration is reduced in lungs adapted to chronic heart failure: morphological and haemodynamic correlates. Cardiovasc. Res. 49, 207–217 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Puri, S. et al. Reduced alveolar-capillary membrane diffusing capacity in chronic heart failure. Its pathophysiological relevance and relationship to exercise performance. Circulation 91, 2769–2774 (1995).

    Article  CAS  PubMed  Google Scholar 

  27. Parissis, J. T. et al. Acute pulmonary oedema: clinical characteristics, prognostic factors, and in-hospital management. Eur. J. Heart Fail. 12, 1193–1202 (2010).

    Article  PubMed  Google Scholar 

  28. Zannad, F. et al. Clinical profile, contemporary management and one-year mortality in patients with severe acute heart failure syndromes: The EFICA study. Eur. J. Heart Fail. 8, 697–705 (2006).

    Article  PubMed  Google Scholar 

  29. Mebazaa, A. et al. The impact of early standard therapy on dyspnoea in patients with acute heart failure: the URGENT-dyspnoea study. Eur. Heart J. 31, 832–841 (2010).

    Article  PubMed  Google Scholar 

  30. Dickstein, K. et al. 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 2008 of the European Society of Cardiology. Eur. Heart J. 29, 2388–2442 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Gossop, M., Keaney, F., Sharma, P. & Jackson, M. The unique role of diamorphine in British medical practice: a survey of general practitioners and hospital doctors. Eur. Addict.Res. 11, 76–82 (2005).

    Article  PubMed  Google Scholar 

  32. McMurray, J. J. et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur. Heart J. 33, 1787–1847 (2012).

    Article  PubMed  Google Scholar 

  33. Vismara, L. A., Leaman, D. M. & Zelis, R. The effects of morphine on venous tone in patients with acute pulmonary oedema. Circulation 54, 335–337 (1976).

    Article  CAS  PubMed  Google Scholar 

  34. Grossmann, M., Abiose, A., Tangphao, O., Blaschke, T. F. & Hoffman, B. B. Morphine-induced venodilation in humans. Clin. Pharmacol. Ther. 60, 554–560 (1996).

    Article  CAS  PubMed  Google Scholar 

  35. Feeney, C., Ani, C., Sharma, N. & Frohlich, T. Morphine-induced cardiogenic shock. Ann. Pharmacother. 45, e30 (2011).

    Article  PubMed  Google Scholar 

  36. Sosnowski, M. A. Review article: lack of effect of opiates in the treatment of acute cardiogenic pulmonary oedema. Emerg. Med. Australas. 20, 384–390 (2008).

    PubMed  Google Scholar 

  37. Peacock, W. F. et al. Morphine and outcomes in acute decompensated heart failure: an ADHERE analysis. Emerg. Med. J. 25, 205–209 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Clark, A. L., Johnson, M. J. & Squire, I. Does home oxygen benefit people with chronic heart failure? BMJ 342, d234 (2011).

    Article  PubMed  Google Scholar 

  39. British Thoracic Society Standards of Care Committee. Non-invasive ventilation in acute respiratory failure. Thorax 57, 192–211 (2002).

  40. Esteban, A., De Elió, F. J., Ancillo, P., Gómez-Acebo, E. & Cerdá, E. Continuous positive pressure ventilation in the management of eight cases of acute pulmonary oedema. Br. J. Anaesth. 45, 1070–1074 (1973).

    Article  CAS  PubMed  Google Scholar 

  41. Simpson, P. M. & Bendall, J. C. Prehospital non-invasive ventilation for acute cardiogenic pulmonary oedema: an evidence-based review. Emerg. Med. J. 28, 609–612 (2011).

    Article  PubMed  Google Scholar 

  42. Peter, J. V., Moran, J. L., Phillips-Hughes, J., Graham, P. & Bersten, A. D. Effect of non-invasive positive pressure ventilation (NIPPV) on mortality in patients with acute cardiogenic pulmonary oedema: a meta-analysis. Lancet 367, 1155–1163 (2006).

    Article  PubMed  Google Scholar 

  43. Gray, A. et al. Noninvasive ventilation in acute cardiogenic pulmonary edema. N. Engl. J. Med. 359, 142–151 (2008).

    Article  CAS  PubMed  Google Scholar 

  44. Dikshit, K. et al. Renal and extrarenal hemodynamic effects of furosemide in congestive heart failure after acute myocardial infarction. N. Engl. J. Med. 288, 1087–1090 (1973).

    Article  CAS  PubMed  Google Scholar 

  45. Larsen, F. F. Haemodynamic effects of high or low doses of furosemide in acute myocardial infarction. Eur. Heart J. 9, 125–131 (1988).

    Article  CAS  PubMed  Google Scholar 

  46. Kiely, J., Kelly, D. T., Taylor, D. R. & Pitt, B. The role of furosemide in the treatment of left ventricular dysfunction associated with acute myocardial infarction. Circulation 48, 581–587 (1973).

    Article  CAS  PubMed  Google Scholar 

  47. Holzer-Richling, N. et al. Randomized placebo controlled trial of furosemide on subjective perception of dyspnoea in patients with pulmonary oedema because of hypertensive crisis. Eur. J. Clin. Invest. 41, 627–634 (2011).

    Article  CAS  PubMed  Google Scholar 

  48. Hayashi, S. Y. et al. Acute effects of low and high intravenous doses of furosemide on myocardial function in anuric haemodialysis patients: a tissue Doppler study. Nephrol. Dial. Transplant. 23, 1355–1361 (2008).

    Article  CAS  PubMed  Google Scholar 

  49. Ikram, H., Chan, W., Espiner, E. A. & Nicholls, M. G. Haemodynamic and hormone responses to acute and chronic frusemide therapy in congestive heart failure. Clin. Sci. 59, 443–449 (1980).

    Article  CAS  Google Scholar 

  50. Towers, K. A., Bardsley, K. A. & Macdonald, P. S. Nebulised frusemide for the symptomatic treatment of end-stage congestive heart failure. Med. J. Aust. 193, 555 (2010).

    Article  PubMed  Google Scholar 

  51. Shimoyama, N. & Shimoyama, M. Nebulized furosemide as a novel treatment for dyspnea in terminal cancer patients. J. Pain Symptom Manage. 23, 73–76 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. Newton, P. J., Davidson, P. M., Krum, H., Ollerton, R. & Macdonald, P. The acute haemodynamic effect of nebulised frusemide in stable, advanced heart failure. Heart Lung Circ. 21, 260–266 (2012).

    Article  CAS  PubMed  Google Scholar 

  53. Adams, K. F. Jr et al. Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am. Heart J. 149, 209–216 (2005).

    Article  PubMed  Google Scholar 

  54. Franciosa, J. A. & Silverstein, S. R. Hemodynamic effects of nitroprusside and furosemide in left ventricular failure. Clin. Pharmacol. Ther. 32, 62–69 (1982).

    Article  CAS  PubMed  Google Scholar 

  55. Nelson, G. I., Silke, B., Ahuja, R. C., Hussain, M. & Taylor, S. H. Haemodynamic advantages of isosorbide dinitrate over furosamide in acute heart failure following myocardial infarction. Lancet 1, 730–732 (1983).

    Article  CAS  PubMed  Google Scholar 

  56. Beltrame, J. F. et al. Nitrate therapy is an alternative to furosemide/morphine therapy in the management of acute cardiogenic pulmonary edema. J. Card. Fail. 4, 271–279 (1998).

    Article  CAS  PubMed  Google Scholar 

  57. Cotter, G. et al. Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema. Lancet 351, 389–393 (1998).

    Article  CAS  PubMed  Google Scholar 

  58. Sharon, A. High-dose intravenous isosorbide-dinitrate is safer and better than Bi-PAP ventilation combined with conventional treatment for severe pulmonary edema. J. Am. Coll. Cardiol. 36, 832–837 (2000).

    Article  CAS  PubMed  Google Scholar 

  59. Hamilton, R. J., Carter, W. A. & Gallagher, E. J. Rapid improvement of acute pulmonary edema with sublingual captopril. Acad. Emerg. Med. 3, 205–212 (1996).

    Article  CAS  PubMed  Google Scholar 

  60. Spieker, L. E. et al. Acute hemodynamic and neurohumoral effects of selective ET(A) receptor blockade in patients with congestive heart failure. ET 003 Investigators. J. Am. Coll. Cardiol. 35, 1745–1752 (2000).

    Article  CAS  PubMed  Google Scholar 

  61. Kaluski, E. et al. RITZ-5: randomized intravenous TeZosentan (an endothelin-A/B antagonist) for the treatment of pulmonary edema: a prospective, multicenter, double-blind, placebo-controlled study. J. Am. Coll. Cardiol. 41, 204–210 (2003).

    Article  CAS  PubMed  Google Scholar 

  62. Teerlink, J. R., Massie, B. M., Cleland, J. G. F. & Tzivoni, D. for the RITZ-1 investigators. A double-blind, parallel-group, multicenter, placebo-controlled study to investigate the efficacy and safety of tezosentan in reducing symptoms in patients with acute decompensated heart failure [abstract]. Circulation 104, II–526 (2001).

    Google Scholar 

  63. McMurray, J. J. et al. Effects of tezosentan on symptoms and clinical outcomes in patients with acute heart failure: the VERITAS randomized controlled trials. JAMA 298, 2009–2019 (2007).

    Article  CAS  PubMed  Google Scholar 

  64. Kohan, D. E., Cleland, J. G., Rubin, L. J., Theodorescu, D. & Barton, M. Clinical trials with endothelin receptor antagonists: What went wrong and where can we improve? Life Sci. 91, 528–539 (2012).

    Article  CAS  PubMed  Google Scholar 

  65. Coletta, A., Thackray, S. & Nikitin, N., Cleland, J. G. Clinical trials update: highlights of the scientific sessions of The American College of Cardiology LIFE, DANAMI 2, MADIT-2, MIRACLE-ICD, OVERTURE, OCTAVE, ENABLE 1 & 2, CHRISTMAS, AFFIRM, RACE, WIZARD, AZACS, REMATCH, BNP trial and HARDBALL. Eur. J. Heart Fail. 4, 381–388 (2002).

    Article  PubMed  Google Scholar 

  66. Mills, R. M. et al. Sustained hemodynamic effects of an infusion of nesiritide (human b-type natriuretic peptide) in heart failure: a randomized, double-blind, placebo-controlled clinical trial. Natrecor Study Group. J. Am. Coll. Cardiol. 34, 155–162 (1999).

    Article  CAS  PubMed  Google Scholar 

  67. Publication Committee for the VMAC Investigators (Vasodilatation in the Management of Acute CHF). Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA 287, 1531–1540 (2002).

  68. O'Connor, C. M. et al. Effect of nesiritide in patients with acute decompensated heart failure. N. Engl. J. Med. 365, 32–43 (2011).

    Article  CAS  PubMed  Google Scholar 

  69. Ando, S., Imaizumi, T., Harada, S., Hirooka, Y. & Takeshita, A. Atrial natriuretic peptide increases human capillary filtration and venous distensibility. J. Hypertens. 10, 451–457 (1992).

    Article  CAS  PubMed  Google Scholar 

  70. Chen, W. et al. Atrial natriuretic peptide enhances microvascular albumin permeability by the caveolae-mediated transcellular pathway. Cardiovasc. Res. 93, 141–151 (2012).

    Article  CAS  PubMed  Google Scholar 

  71. Debrah, D. O., Conrad, K. P., Jeyabalan, A., Danielson, L. A. & Shroff, S. G. Relaxin increases cardiac output and reduces systemic arterial load in hypertensive rats. Hypertension 46, 745–750 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Teerlink, J. R. et al. Relaxin for the treatment of patients with acute heart failure (Pre-RELAX-AHF): a multicentre, randomised, placebo-controlled, parallel-group, dose-finding phase IIb study. Lancet 373, 1429–1439 (2009).

    Article  CAS  PubMed  Google Scholar 

  73. Teerlink, J. R. et al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet http://dx.doi.org/10.1016/S0140-6736(12)61855-8.

  74. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  75. Sartori, C., Matthay, M. A. & Scherrer, U. Transepithelial sodium and water transport in the lung. Major player and novel therapeutic target in pulmonary edema. Adv. Exp. Med. Biol. 502, 315–338 (2001).

    Article  CAS  PubMed  Google Scholar 

  76. Matthay, M. A., Folkesson, H. G. & Clerici, C. Lung epithelial fluid transport and the resolution of pulmonary edema. Physiol. Rev. 82, 569–600 (2002).

    Article  CAS  PubMed  Google Scholar 

  77. Mutlu, G. M. et al. Upregulation of alveolar epithelial active Na+ transport is dependent on beta2-adrenergic receptor signaling. Circ. Res. 94, 1091–1100 (2004).

    Article  CAS  PubMed  Google Scholar 

  78. Mutlu, G. M. & Factor, P. Alveolar epithelial beta2-adrenergic receptors. Am. J. Respir. Cell. Mol. Biol. 38, 127–134 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Maak, C. A., Tabas, J. A. & McClintock, D. E. Should acute treatment with inhaled beta agonists be withheld from patients with dyspnea who may have heart failure? J. Emerg. Med. 40, 135–145 (2011).

    Article  PubMed  Google Scholar 

  80. Thorneloe, K. S. et al. An orally active TRPV4 channel blocker prevents and resolves pulmonary edema in heart failure. Sci. Transl. Med. 4, 159ra148 (2012).

    Article  PubMed  CAS  Google Scholar 

  81. Gheorghiade, M. et al. Cinaciguat, a soluble guanylate cyclase activator: results from the randomized, controlled, phase IIb COMPOSE programme in acute heart failure syndromes. Eur. J. Heart Fail. 14, 1056–1066 (2012).

    Article  CAS  PubMed  Google Scholar 

  82. Benz, K. et al. Blood pressure-independent effect of long-term treatment with the soluble heme-independent guanylyl cyclase activator HMR1766 on progression in a model of noninflammatory chronic renal damage. Kidney Blood Press. Res. 30, 224–233 (2007).

    Article  CAS  PubMed  Google Scholar 

  83. Jones, E. S., Kemp-Harper, B., Stasch, J. P., Schmidt, H. & Widdop, R. E. Cardioprotective effects in aged spontaneously hypertensive rats due to chronic stimulation/activation of sGC without hypotension. BMC Pharmacol. 9 (Suppl. 1), P29 (2009).

    Article  PubMed Central  Google Scholar 

  84. Capomolla, S. et al. Chronic infusion of dobutamine and nitroprusside in patients with end-stage heart failure awaiting heart transplantation: safety and clinical outcome. Eur. J. Heart Fail. 3, 601–610 (2001).

    Article  CAS  PubMed  Google Scholar 

  85. Thackray, S., Easthaugh, J., Freemantle, N. & Cleland, J. G. The effectiveness and relative effectiveness of intravenous inotropic drugs acting through the adrenergic pathway in patients with heart failure-a meta-regression analysis. Eur. J. Heart Fail. 4, 515–529 (2002).

    Article  CAS  PubMed  Google Scholar 

  86. Follath, F. et al. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial. Lancet 360, 196–202 (2002).

    Article  CAS  PubMed  Google Scholar 

  87. Mebazaa, A. et al. Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE Randomized Trial. JAMA 297, 1883–1891 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. Landoni, G. et al. Effects of levosimendan on mortality and hospitalization. A meta-analysis of randomized controlled studies. Crit. Care Med. 40, 634–646 (2012).

    Article  CAS  PubMed  Google Scholar 

  89. Bragadeesh, T. K., Mathur, G., Clark, A. L. & Cleland, J. G. Novel cardiac myosin activators for acute heart failure. Expert Opin. Investig. Drugs 16, 1541–1548 (2007).

    Article  CAS  PubMed  Google Scholar 

  90. Cleland, J. G. et al. The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial. Lancet 378, 676–683 (2011).

    Article  CAS  PubMed  Google Scholar 

  91. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  92. Gheorghiade, M. et al. Hemodynamic, echocardiographic, and neurohormonal effects of istaroxime, a novel intravenous inotropic and lusitropic agent: a randomized controlled trial in patients hospitalized with heart failure. J. Am. Coll. Cardiol. 51, 2276–2285 (2008).

    Article  CAS  PubMed  Google Scholar 

  93. Shah, S. J. et al. Effects of istaroxime on diastolic stiffness in acute heart failure syndromes: results from the Hemodynamic, Echocardiographic, and Neurohormonal Effects of Istaroxime, a Novel Intravenous Inotropic and Lusitropic Agent: a Randomized Controlled Trial in Patients Hospitalized with Heart Failure (HORIZON-HF) trial. Am. Heart J. 157, 1035–1041 (2009).

    Article  CAS  PubMed  Google Scholar 

  94. Thiele, H. et al. Intraaortic balloon counterpulsation in acute myocardial infarction complicated by cardiogenic shock: design and rationale of the Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial. Am. Heart J. 163, 938–945 (2012).

    Article  PubMed  Google Scholar 

  95. Thiele, H. et al. Intraaortic balloon support for myocardial infarction with cardiogenic shock. N. Engl. J. Med. 163, 938–945 (2012).

    Google Scholar 

  96. Engström, A. E. et al. The Impella 2.5 and 5.0 devices for ST-elevation myocardial infarction patients presenting with severe and profound cardiogenic shock: the Academic Medical Center intensive care unit experience. Crit. Care Med. 39, 2072–2079 (2011).

    Article  PubMed  Google Scholar 

  97. Stack, R. S., Stack, R. K., Morris, K. G., Bauman, R. P. & Shadoff, N. Temporary balloon occlusion of the inferior vena cava for immediate reversal of acute pulmonary edema. Am. J. Cardiol. 57, 886–887 (1986).

    Article  CAS  PubMed  Google Scholar 

  98. Warner, G. F., Dobson, E. L., Rodgers, C. E., Johnston, M. E. & Pace, N. The measurement of total “sodium space” and total body sodium in normal individuals and in patients with cardiac edema. Circulation 5, 915–919 (1952).

    Article  CAS  PubMed  Google Scholar 

  99. Cleland, J. G., Dargie, H. J., Robertson, I., Robertson, J. I. & East, B. W. Total body electrolyte composition in patients with heart failure: a comparison with normal subjects and patients with untreated hypertension. Br. Heart J. 58, 230–238 (1987).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  100. Anand, I. S. et al. Edema of cardiac origin. Studies of body water and sodium, renal function, hemodynamic indexes, and plasma hormones in untreated congestive cardiac failure. Circulation 80, 299–305 (1989).

    Article  CAS  PubMed  Google Scholar 

  101. Harris, P. Evolution and the cardiac patient. Cardiovasc. Res. 17, 313–319, 373–378, 437–345 (1983).

    Article  CAS  PubMed  Google Scholar 

  102. Franklin, S. S., et al. Hemodynamic patterns of age-related changes in blood pressure. The Framingham Heart Study. Circulation 96, 308–315 (1997).

    Article  CAS  PubMed  Google Scholar 

  103. Merrill, A. J. Edema and decreased renal blood flow in patients with chronic congestive heart failure: evidence of “forward failure” as primary cause of edema. J. Clin. Invest. 25, 389–400 (1946).

    Article  PubMed Central  PubMed  Google Scholar 

  104. Skinner, S. L., McCubbin, J. W. & Page, I. H. Control of renin secretion. Circ. Res. 15, 64–76 (1964).

    Article  CAS  PubMed  Google Scholar 

  105. Farhi, E. R., Cant, J. R. & Barger, A. C. Interactions between intrarenal epinephrine receptors and the renal baroreceptor in the control of PRA in conscious dogs. Circ. Res. 50, 477–485 (1982).

    Article  CAS  PubMed  Google Scholar 

  106. Knepper, M. A. Molecular physiology of urinary concentrating mechanism: regulation of aquaporin water channels by vasopressin. Am. J. Physiol. Renal Physiol. 41, F3–F12 (1997).

    Article  Google Scholar 

  107. Bonjour, J. P. & Malvin, R. L. Stimulation of ADH release by the renin-angiotensin system. Am. J. Physiol. 218, 1555–1559 (1970).

    Article  CAS  PubMed  Google Scholar 

  108. Szatalowicz, V. L. et al. Radioimmunoassay of plasma arginine vasopressin in hyponatremic patients with congestive heart failure. N. Engl. J. Med. 305, 263–266 (1981).

    Article  CAS  PubMed  Google Scholar 

  109. Francis, G. S. et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation 82, 1724–1729.

    Article  CAS  PubMed  Google Scholar 

  110. Robertson, G. L. Regulation of arginine vasopressin in the syndrome of inappropriate antidiuresis. Am. J. Med. 119 (Suppl. 1), S36–S42 (2006).

    Article  CAS  PubMed  Google Scholar 

  111. Nordgren, L. & Sörensen, S. Symptoms experienced in the last six months of life in patients with end-stage heart failure. Eur. J. Cardiovasc. Nurs. 2, 213–217 (2003).

    Article  PubMed  Google Scholar 

  112. Falk, S., Wahn, A.-K. & Lidell, E. Keeping the maintenance of daily life in spite of chronic heart failure. A qualitative study. Eur. J. Cardiovasc. Nurs. 6, 192–199 (2007).

    Article  PubMed  Google Scholar 

  113. Waldréus, N., Sjöstrand, F. & Hahn, R. G. Thirst in the elderly with and without heart failure. Arch. Gerontol. Geriatr. 53, 174–178 (2011).

    Article  PubMed  Google Scholar 

  114. Farrell, M. J. et al. Effect of aging on regional cerebral blood flow responses associated with osmotic thirst and its satiation by water drinking: a PET study. Proc. Natl Acad. Sci. USA 105, 382–387 (2008).

    Article  CAS  PubMed  Google Scholar 

  115. Ramsay, D. J., Rolls, B. J. & Wood, R. J. The relationship between elevated water intake and oedema associated with congestive cardiac failure in the dog. J. Physiol. 244, 303–312 (1975).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  116. Johnson, A. K., Mann, J. F., Rascher, W., Johnson, J. K. & Ganten, D. Plasma angiotensin II concentrations and experimentally induced thirst. Am. J. Physiol. 240, R229–R234 (1981).

    CAS  PubMed  Google Scholar 

  117. Szczepanska-Sadowska, E., Sobocinska, J. & Sadowski, B. Central dipsogenic effect of vasopressin. Am. J. Physiol. 242, R372–R379 (1982).

    CAS  PubMed  Google Scholar 

  118. Travers, B. et al. Fluid restriction in the management of decompensated heart failure: no impact on time to clinical stability. J. Card. Fail. 13, 128–132 (2007).

    Article  PubMed  Google Scholar 

  119. Holst, M., Strömberg, A., Lindholm, M. & Willenheimer, R. Liberal versus restricted fluid prescription in stabilised patients with chronic heart failure: result of a randomised cross-over study of the effects on health-related quality of life, physical capacity, thirst and morbidity. Scand. Cardiovasc. J. 42, 316–322 (2008).

    Article  PubMed  Google Scholar 

  120. Abildgaard, U. et al. Bed rest and increased diuretic treatment in chronic congestive heart failure. Eur. Heart J. 6, 1040–1046 (1985).

    Article  CAS  PubMed  Google Scholar 

  121. McDonald, C. D., Burch, G. E. & Walsh, J. J. Prolonged bed rest in the treatment of idiopathic cardiomyopathy. Am. J. Med. 52, 41–50 (1972).

    Article  CAS  PubMed  Google Scholar 

  122. Flapan, A. D. et al. The influence of posture on the response to loop diuretics in patients with chronic cardiac failure is reduced by angiotensin converting enzyme inhibition. Eur. J. Clin. Pharmacol. 42, 581–585 (1992).

    Article  CAS  PubMed  Google Scholar 

  123. Miller, W. L., Bailey, K. R., Weston, S. A., Burnett, J. C. Jr & Rodeheffer, R. J. Hemodynamic and plasma atrial natriuretic peptide responses to acute digitalis therapy in patients with normal and impaired left ventricular function. Eur. J. Heart Fail. 4, 63–72 (2002).

    Article  CAS  PubMed  Google Scholar 

  124. CLOTS (Clots in Legs Or sTockings after Stroke) Trial Collaboration. Thigh-length versus below-knee stockings for deep venous thrombosis prophylaxis after stroke: a randomized trial. Ann. Intern. Med. 153, 553–562 (2010).

  125. de Silva, R. Incidence of renal dysfunction over 6 months in patients with chronic heart failure due to left ventricular systolic dysfunction: contributing factors and relationship to prognosis. Eur. Heart J. 27, 569–581 (2006).

    Article  CAS  PubMed  Google Scholar 

  126. Maxwell, A. P., Ong, H. Y. & Nicholls, D. P. Influence of progressive renal dysfunction in chronic heart failure. Eur. J. Heart Fail. 4, 125–130 (2002).

    Article  PubMed  Google Scholar 

  127. Cleland, J. G. et al. Renal dysfunction in acute and chronic heart failure: prevalence, incidence and prognosis. Heart Fail. Rev. 17, 133–149 (2012).

    Article  CAS  PubMed  Google Scholar 

  128. Harjola, V. P. et al. Characteristics, outcomes, and predictors of mortality at 3 months and 1 year in patients hospitalized for acute heart failure. Eur. J. Heart Fail. 12, 239–248 (2010).

    Article  PubMed  Google Scholar 

  129. Elkayam, U. et al. Renal circulatory effects of adenosine in patients with chronic heart failure. J. Am. Coll. Cardiol. 32, 211–215 (1998).

    Article  CAS  PubMed  Google Scholar 

  130. Massie, B. M. et al. Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure. N. Engl. J. Med. 363, 1419–1428 (2010).

    Article  PubMed  Google Scholar 

  131. Dormans, T. P., Gerlag, P. G., Russel, F. G. & Smits, P. Combination diuretic therapy in severe congestive heart failure. Drugs 2, 165–172 (1998).

    Article  Google Scholar 

  132. Brater, D. C. Pharmacology of diuretics. Am. J. Med. Sci. 319, 38–50 (2000).

    Article  CAS  PubMed  Google Scholar 

  133. Pothuizen, L. M. & Chada, D. R. Treatment of congestive cardiac failure in elderly patients: randomised study of hydrochlorothiazide and slow release furosemide. Curr. Ther. Res. 32, 513–519 (1982).

    Google Scholar 

  134. Vermeulen, A. & Chada, D. R. Slow-release furosemide and hydrochlorothiazide in congestive cardiac failure: A controlled trial. J. Clin. Pharmacol. 22, 513–519 (1982).

    Article  CAS  PubMed  Google Scholar 

  135. Krause, U., Zielke, A., Schmidt-Gayk, H., Ehrenthal, W. & Beyer, J. Direct tubular effect on calcium retention by hydrochlorothiazide. J. Endocrinol. Invest. 12, 531–535 (1989).

    Article  CAS  PubMed  Google Scholar 

  136. Solomon, D. H., Mogun, H., Garneau, K. & Fischer, M. A. Risk of fractures in older adults using antihypertensive medications. J. Bone Miner. Res. 26, 1561–1567 (2011).

    Article  CAS  PubMed  Google Scholar 

  137. Dargie, H. J., Allison, M. E., Kennedy, A. C. & Gray, M. H. High dose metolazone in chronic renal failure. Br. Med. J. 4, 196–198 (1972).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  138. Kohvakka, A. Maintenance of potassium balance during long-term diuretic therapy in chronic heart failure patients with thiazide induced hypokalemia: comparison of potassium supplementation with potassium chloride and potassium-sparing agents, amiloride and triamterene. Int. J. Clin. Pharmacol. Ther. Toxicol. 26, 273–277 (1988).

    CAS  PubMed  Google Scholar 

  139. Pitt, B. et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N. Engl. J. Med. 341, 709–717 (1999).

    Article  CAS  PubMed  Google Scholar 

  140. Zannad, F. et al. Eplerenone in patients with systolic heart failure and mild symptoms. N. Engl. J. Med. 364, 11–21 (2011).

    Article  CAS  PubMed  Google Scholar 

  141. Stewart, J. H. & Edwards, K. D. G. Clinical comparison of frusemide with bendrofluazide, mersalyl and ethacrynic acid. Br. Med. J. 2, 1277–1281 (1965).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  142. Kaissling, B. & Stanton, B. A. Adaptation of distal tubule and collecting duct to increased sodium delivery: I Ultrastructure. Am. J. Physiol. 255, F1256–F1275 (1988).

    CAS  PubMed  Google Scholar 

  143. Stanton, B. A. & Kaissling, B. Adaptation of distal tubule and collecting duct to increased Na delivery. II. Na and K transport. Am. J. Physiol. 255, 1269–1275 (1988).

    Google Scholar 

  144. Murray, M. D., Haag, K. M., Black, P. K., Hall, S. D. & Brater, D. C. Variable furosemide absorption and poor predictability of response in elderly patients. Pharmacother. 17, 98–106 (1997).

    CAS  Google Scholar 

  145. Vasko, M. R., Cartwright, D. B., Knochel, J. P. Nixon, J. V. & Brater, D. C. Furosemide absorption altered in decompensated congestive heart failure. Ann. Intern. Med. 102, 314–318 (1985).

    Article  CAS  PubMed  Google Scholar 

  146. van Meyel, J. J. et al. Continuous infusion of furosemide in the treatment of patients with congestive heart failure and diuretic resistance. J. Intern. Med. 235, 329–334 (1994).

    Article  CAS  PubMed  Google Scholar 

  147. Dormans, T. P. et al. Diuretic efficacy of high dose furosemide in severe heart failure: bolus versus continuous infusion. J. Am. Coll. Cardiol. 28, 376–382 (1996).

    Article  CAS  PubMed  Google Scholar 

  148. Lahav, M., Regev, A., Ra'anani, P. & Theodor, E. Intermittent administration of furosemide vs continuous infusion preceded by a loading dose for congestive heart failure. Chest 102, 725–731 (1992).

    Article  CAS  PubMed  Google Scholar 

  149. Pivac, N. et al. Diuretic effects of furosemide infusion versus bolus injection in congestive heart failure. Int. J. Clin. Pharmacol. Res. 18, 121–128 (1998).

    CAS  PubMed  Google Scholar 

  150. Paterna, S. et al. Effects of high dose furosemide and small volume hypertonic saline solution infusion in comparison with a high dose of furosemide as a bolus, in refractory congestive heart failure. Eur. J. Heart Fail. 2, 305–313 (2000).

    Article  CAS  PubMed  Google Scholar 

  151. Rudy, D. W., Voelker, J. R., Greene, P. K., Esparza, F. A. & Brater, D. C. Loop diuretics for renal insufficiency: a continuous infusion is more efficacious than bolus therapy. Ann. Intern. Med. 115, 360–366 (1991).

    Article  CAS  PubMed  Google Scholar 

  152. Felker, G. M. et al. Diuretic strategies in patients with acute decompensated heart failure. N. Engl. J. Med. 364, 797–805 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  153. Sigured, B., Olesen, K. H. & Wennevold, A. The supra-additive natriuretic effect of addition of bendroflumethiazide and bumetanide in congestive heart failure. Am. Heart J. 89, 163–170 (1975).

    Article  Google Scholar 

  154. Channer, K. S., McLean, K. A., Lawson-Matthew, P. & Richardson, M. Combination diuretic treatment in severe heart failure: a randomised controlled trial. Br. Heart J. 71, 146–150 (1994).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  155. Bartoli, E. et al. Blunting of furosemide diuresis by aspirin in man. J. Clin. Pharmacol. 20, 452–458 (1980).

    Article  CAS  PubMed  Google Scholar 

  156. Jondeau, G. et al. B-CONVINCED: Beta-blocker CONtinuation Vs. INterruption in patients with Congestive heart failure hospitalizED for a decompensation episode. Eur. Heart J. 30, 2186–2192 (2009).

    Article  CAS  PubMed  Google Scholar 

  157. Metra, M. et al. Should beta-blocker therapy be reduced or withdrawn after an episode of decompensated heart failure? Results from COMET. Eur. J. Heart Fail. 9, 901–909 (2007).

    Article  CAS  PubMed  Google Scholar 

  158. [No authors listed] The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group. N. Engl. J. Med. 336, 525–533 (1997).

  159. Gavey, C. J. & Parkinson, J. Digitalis in heart failure with normal rhythm. Br. Heart J. 1, 27–44 (1939).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  160. Ahmed, A. et al. Digoxin and reduction in mortality and hospitalization in heart failure: a comprehensive post hoc analysis of the DIG trial. Eur. Heart J. 27, 178–186 (2006).

    Article  CAS  PubMed  Google Scholar 

  161. Kolff, W. J. & Leonards, J. R. Reduction of otherwise intractable edema by dialysis or filtration. Cleveland Clin. Q. 21, 61–71 (1954).

    Article  CAS  Google Scholar 

  162. Marenzi, G. et al. Circulatory response to fluid overload removal by extracorporeal ultrafiltration in refractory congestive heart failure. J. Am. Coll. Cardiol. 38, 963–968 (2001).

    Article  CAS  PubMed  Google Scholar 

  163. Bart, B. A. et al. Ultrafiltration versus usual care for hospitalized patients with heart failure: the Relief for Acutely Fluid-Overloaded Patients With Decompensated Congestive Heart Failure (RAPID-CHF) trial. J. Am. Coll. Cardiol. 46, 2043–2046 (2005).

    Article  PubMed  Google Scholar 

  164. Libetta, C. et al. Intermittent haemodiafiltration in refractory congestive heart failure: BNP and balance of inflammatory cytokines. Nephrol. Dial. Transplant. 22, 2013–2019 (2007).

    Article  CAS  PubMed  Google Scholar 

  165. Costanzo, M. R. et al. Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J. Am. Coll. Cardiol. 49, 675–683 (Erratum. J. Am. Coll. Cardiol. 49, 1136 [2007]).

    Article  CAS  PubMed  Google Scholar 

  166. Agostoni, P. et al. Sustained improvement in functional capacity after removal of body fluid with isolated ultrafiltration in chronic cardiac insufficiency: failure of furosemide to provide the same result. Am. J. Med. 96, 191–199 (1994).

    Article  CAS  PubMed  Google Scholar 

  167. Ali, S. S. et al. Loop diuretics can cause clinical natriuretic failure: a prescription for volume expansion. Congest. Heart Fail. 15, 1–4 (2009).

    Article  CAS  PubMed  Google Scholar 

  168. Costanzo, M. R., Saltzberg, M., O'Sullivan, J. & Sobotka, P. Early ultrafiltration in patients with decompensated heart failure and diuretic resistance. J. Am. Coll. Cardiol. 46, 2047–2051 (2005).

    Article  PubMed  Google Scholar 

  169. Patarroyo, M. et al. Cardiorenal outcomes after slow continuous ultrafiltration therapy in refractory patients with advanced decompensated heart failure. J. Am. Coll. Cardiol. 60, 1906–1912 (2012).

    Article  PubMed  Google Scholar 

  170. Bart, B. A. et al. Cardiorenal rescue study in acute decompensated heart failure: rationale and design of CARRESS-HF, for the Heart Failure Clinical Research Network. J. Card. Fail. 18, 176–182 (2012).

    Article  PubMed Central  PubMed  Google Scholar 

  171. Bart, B. A. et al. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N. Engl. J. Med. 367, 2296–2304 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  172. Lee, W. H. & Packer, M. Prognostic importance of serum sodium concentration and its modification by converting-enzyme inhibition in patients with severe chronic heart failure. Circulation 73, 257–267 (1986).

    Article  CAS  PubMed  Google Scholar 

  173. Francis, G. S. et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation 82, 1724–1729 (1990).

    Article  CAS  PubMed  Google Scholar 

  174. Licata, G. et al. Effects of high-dose furosemide and small-volume hypertonic saline solution infusion in comparison with a high dose of furosemide as bolus in refractory congestive heart failure: long-term effects. Am. Heart J. 145, 459–466 (2003).

    Article  CAS  PubMed  Google Scholar 

  175. Paterna, S. et al. Changes in brain natriuretic peptide levels and bioelectrical impedance measurements after treatment with high-dose furosemide and hypertonic saline solution versus high-dose furosemide alone in refractory congestive heart failure: a double-blind study. J. Am. Coll. Cardiol. 45, 1997–2003 (2005).

    Article  CAS  PubMed  Google Scholar 

  176. Paterna, S., Gaspare, P., Fasullo, S., Sarullo, F. M. & Di Pasquale, P. Normal-sodium diet compared with low-sodium diet in compensated congestive heart failure: is sodium an old enemy or a new friend? Clin. Sci. (Lond.) 114, 221–230 (2008).

    Article  CAS  Google Scholar 

  177. Dinicolantonio, J. J., Pasquale, P. D., Taylor, R. S. & Hackam, D. G. Low sodium versus normal sodium diets in systolic heart failure: systematic review and meta-analysis. Heart http://dx.doi.org/10.1136/heartjnl-2012-302337.

  178. Packer, M., Medina, N. & Yushak, M. Correction of dilutional hyponatremia in severe chronic heart failure by converting-enzyme inhibition. Ann. Intern. Med. 100, 782–789 (1984).

    Article  CAS  PubMed  Google Scholar 

  179. Gheorghiade, M. et al. Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: results from a double-blind, randomized trial. Circulation 107, 2690–2696 (2003).

    Article  CAS  PubMed  Google Scholar 

  180. Konstam, M. A. et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA 297, 1319–1331 (2007).

    Article  CAS  PubMed  Google Scholar 

  181. Cowburn, P. J., Patel, H., Jolliffe, R. E., Wald, R. W. & Parker, J. D. Cardiac resynchronization therapy: an option for inotrope-supported patients with end-stage heart failure? Eur. J. Heart Fail. 7, 215–217 (2005).

    Article  PubMed  Google Scholar 

  182. Anker, S. D., Koehler, F. & Abraham, W. T. Telemedicine and remote management of patients with heart failure. Lancet 378, 731–739 (2011).

    Article  PubMed  Google Scholar 

  183. Cleland, J. G. & Clark, A. L. Delivering the cumulative benefits of triple therapy to improve outcomes in heart failure: too many cooks will spoil the broth. J. Am. Coll. Cardiol. 42, 1234–1237 (2003).

    Article  PubMed  Google Scholar 

  184. Shelton, R. J., Clark, A. L., Kaye, G. C. & Cleland, J. G. The atrial fibrillation paradox of heart failure. Congest. Heart Fail. 16, 3–9 (2010).

    Article  CAS  PubMed  Google Scholar 

  185. Clark, A. L., Goode, K. & Cleland, J. G. The prevalence and incidence of left bundle branch block in ambulant patients with chronic heart failure. Eur. J. Heart Fail. 10, 696–702 (2008).

    Article  PubMed  Google Scholar 

  186. QS9 Quality heart failure quality standard. National Institute for Health and Clinical Excellence [online], (2012).

  187. Voors, A. A. et al. Effects of the adenosine A1 receptor antagonist rolofylline on renal function in patients with acute heart failure and renal dysfunction: results from PROTECT (Placebo-Controlled Randomized Study of the Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function). J. Am. Coll. Cardiol. 57, 1899–1907 (2011).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cardiology, Hull York Medical School, University of Hull, Castle Hill Hospital, Cottingham, HU16 5JQ, UK

    Andrew L. Clark & John G. F. Cleland

Authors
  1. Andrew L. Clark
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John G. F. Cleland
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Both authors researched data for article, and made substantial contribution to discussion of content and to reviewing and editing of manuscript before submission. A. L. Clark wrote the article.

Corresponding author

Correspondence to Andrew L. Clark.

Ethics declarations

Competing interests

A. L. Clark declares that he is on the advisory board for Novartis. J. G. F. Cleland declares that he has been a consultant for and received grants from Amgen and Novartis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Clark, A., Cleland, J. Causes and treatment of oedema in patients with heart failure. Nat Rev Cardiol 10, 156–170 (2013). https://doi.org/10.1038/nrcardio.2012.191

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrcardio.2012.191

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing