Congestive heart failure laboratory tests: Difference between revisions

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Revision as of 19:37, 7 October 2018

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Lakshmi Gopalakrishnan, M.B.B.S. [2]; Seyedmahdi Pahlavani, M.D. [3]; Tarek Nafee, M.D. [4]

Overview

BNP levels may be useful in the initial establishment of the diagnosis of heart failure in the patient with dyspnea of unclear etiology. In a meta-analysis, BNP was superior N-terminal pro-BNP (NTproBNP) and was associated with a sensitivity of 85% and specificity of 84% in the diagnosis of heart failure in the primary care setting.^[1] Once the diagnosis of heart failure is made, subsequent laboratory studies should be directed toward the identification of an underlying cause of heart failure.

Laboratory Tests

Renal Function

Renal function should be assessed as a rough guide to the patient's intravascular volume status and renal perfusion. A urinalysis is helpful in the assessment of the patient's volume status. Electrolyte assessment and the correction of electrolyte disturbances such as hypokalemia, hyperkalemia and hypomagnesemia is critical in those patients treated with diuretics. Hyponatremia (due to poor stimulation of the baroreceptors and appropriate ADH release and free water retention) is associated with a poor prognosis.

Hematologic Studies

A complete blood count should be obtained to assess for the presence of anemia which may exacerbate heart failure and to assess the patients coagulation status which may be impaired due to hepatic congestion.

Thyroid Studies

The assessment of thyroid function tests is particularly important in the patient who is being treated with concomitant therapy with an agent such as amiodarone.

Biomarkers

Biomarkers are going to play a great role in diagnosis of heart failure.

Natriuretic Peptides: BNP or NT-proBNP

BNP or its amino-terminal cleavage equivalent (NT-proBNP) is generated by cardiomyocytes in the context of numerous triggers, most notably myocardial stretch. These biomarkers have been studied for the detection of elevated cardiac pressured^[2]^[3]^[4], low ejection fraction^[5], or both^[6].

Clinical practice guidelines suggest their measurement is helpful for diagnosis or ruling out heart failure especially in acute setting.^[7]

	Cardiac cause	Non cardiac causes
Elevated BNP	Heart failure Acute coronary syndrome Heart muscle disease, including LVH Valvular heart disease Pericardial disease Atrial fibrillation Myocarditis Cardiac surgery Cardioversion	Advancing age Anemia Renal failure Pulmonary: obstructive sleep apnea, severe pneumonia, pulmonary hypertension Critical illness Bacterial sepsis Severe burns Toxic-metabolic insults, including cancer chemotherapy and envenomation

Biomarkers indications for use

Abbreviations: ACC: American College of Cardiology, AHA: American Heart Association, ADHF: acute decompensated heart failure, BNP: B-type natriuretic peptide, COR: Class of Recommendation, ED: emergency department, HF: heart failure, NT-proBNP: N-terminal pro-B-type natriuretic peptide, NYHA: New York Heart Association, pts: patients

(*)Other biomarkers of injury or fibrosis include soluble ST2 receptor, galectin-3, and high-sensitivity troponin.

Biomarkers of Myocardial Injury: Cardiac Troponin T or I

Even without obvious myocardial ischemic injury, troponin level may be increased in heart failure which means undergoing myocyte injury.^[8] Elevated levels of troponin is associated with impaired hemodynamics, progressive LV dysfunction and increased mortality rates.^[9]

Carbohydrate Antigen 125

CA-125 is an emerging, highly sensitive biomarker for heart failure.^[10] Although it is not yet used in clinical practice, the CHANCE-HF trial has demonstrated utility in using CA-125 to guide diuretic therapy and for determining short-term prognosis.^[11] CA-125 is a non-specific antigen that is most strongly associated with ovarian cancer. In patients with acute heart failure, ambulatory follow-up care aimed at titrating diuretic use according to CA-125 levels has demonstrated ~50% reduction in rehospitalizations.^[11] CA-125 was first associated with heart failure in 1999 by Nagele et al.^[10]^[12]

2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure/2013 ACCF/AHA Guideline for the Management of Heart Failure/2009 ACC/AHA Focused Update and 2005 Guidelines for the Diagnosis and Management of Chronic Heart Failure in the Adult (DO NOT EDIT)^[13]^[14]

Initial Clinical Assessment of Patients Presenting With Heart Failure (DO NOT EDIT)^[13]^[14]

Class I
"1. Initial laboratory evaluation of patients presenting with heart failure should include complete blood count, urinalysis, serum electrolytes (including calcium and magnesium), blood urea nitrogen, serum creatinine, fasting blood glucose (glycohemoglobin), lipid profile, liver function tests, and thyroid-stimulating hormone. (Level of Evidence: C) "
"2. Serial monitoring, when indicated, should include serum electrolytes and renal function. (Level of Evidence: C) "
"3. A 12-lead ECG should be performed initially on all patients presenting with HF. (Level of Evidence: C) "
"4. In ambulatory patients with dyspnea, measurement of BNP or N-terminal pro-B-type natriuretic peptide (NT-proBNP) is useful to support clinical decision making regarding the diagnosis of HF, especially in the setting of clinical uncertainty.^[15]^[16] (Level of Evidence: A) "
"5. In hospitalized patients/acute setting, measurement of BNP or NT-proBNP is useful to support clinical judgment for the diagnosis of acutely decompensated HF, especially in the setting of uncertainty for the diagnosis.^[17]^[18] (Level of Evidence: A) "
"6. In hospitalized patients/acute setting, Measurement of BNP or NT-proBNP and/or cardiac troponin is useful for establishing prognosis or disease severity in acutely decompensated HF.^[19]^[20] (Level of Evidence: A) "
"7. Measurement of BNP or NT-proBNP is useful for establishing prognosis or disease severity in chronic HF.^[21]^[22]^[23](Level of Evidence: A) "

Class III (No Benefit)
"1. Routine measurement of circulating levels of neurohormones (e.g., norepinephrine or endothelin) is not recommended for patients presenting with heart failure. (Level of Evidence: C) "

Class IIa
"1. BNP- or NT-proBNP–guided HF therapy can be useful to achieve optimal dosing of GDMT in select clinically euvolemic patients followed in a well-structured HF disease management program. (Level of Evidence: B) "
"2. Screening for hemochromatosis or HIV is reasonable in selected patients who present with HF (Level of Evidence: C) "
"3. Diagnostic tests for rheumatologic diseases, amyloidosis, or pheochromocytoma are reasonable in patients presenting with heart failure in whom there is a clinical suspicion of these diseases. (Level of Evidence: C) "

Serial Clinical Assessment of Patients Presenting With Heart Failure (DO NOT EDIT)^[13]^[14]

Class IIb
"1. The usefulness of serial measurement of BNP or NT-proBNP to reduce hospitalization or mortality in patients with HF is not well established. (Level of Evidence: B) "
"2. The usefulness of BNP- or NT-proBNP–guided therapy for acutely decompensated HF is not well established. (Level of Evidence: C) "
"3. Measurement of other clinically available tests such as biomarkers of myocardial injury or fibrosis may be considered for additive risk stratification in patients with acutely decompensated HF. (Level of Evidence: A) "
"4. Measurement of other clinically available tests such as biomarkers of myocardial injury or fibrosis may be considered for additive risk stratification in patients with chronic HF. (Level of Evidence: B) "

Biomarkers for Prevention (DO NOT EDIT)

Class IIa
"1. For patients at risk of developing HF, natriuretic peptide biomarker–based screening followed by team-based care, including a cardiovascular specialist optimizing GDMT, can be useful to prevent the development of left ventricular dysfunction (systolic or diastolic) or new-onset HF.^[24]^[25] (Level of Evidence: B-R) "

Biomarkers for Diagnosis (DO NOT EDIT)

Class I
"1. In patients presenting with dyspnea, measurement of natriuretic peptide biomarkers is useful to support a diagnosis or exclusion of HF.^[26]^[21]^[27] (Level of Evidence: A) "

Biomarkers for Prognosis or Added Risk Stratification (DO NOT EDIT)

Class I
"1. Measurement of BNP or NT-proBNP is useful for establishing prognosis or disease severity in chronic HF.^[21]^[28] (Level of Evidence: A) "
"2. Measurement of baseline levels of natriuretic peptide biomarkers and/or cardiac troponin on admission to the hospital is useful to establish a prognosis in acutely decompensated HF.^[19]^[20]^[29]^[30] (Level of Evidence: A) "

Class IIa
"1. During a HF hospitalization, a predischarge natriuretic peptide level can be useful to establish a postdischarge prognosis.^[20]^[31]^[32] (Level of Evidence: B-NR) "

Class IIb
"1. In patients with chronic HF, measurement of other clinically available tests, such as biomarkers of myocardial injury or fibrosis, may be considered for additive risk stratification.^[29]^[33]^[30] (Level of Evidence: B-NR) "

Vote on and Suggest Revisions to the Current Guidelines

The CHF Living Guidelines: Vote on current recommendations and suggest revisions to the guidelines

Sources

The ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult ^[13]

2009 focused update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation ^[14]

References

↑ Ewald B, Ewald D, Thakkinstian A, Attia J (2008). "Meta-analysis of B type natriuretic peptide and N-terminal pro B natriuretic peptide in the diagnosis of clinical heart failure and population screening for left ventricular systolic dysfunction". Intern Med J. 38 (2): 101–13. doi:10.1111/j.1445-5994.2007.01454.x. PMID 18290826.
↑ Dokainish H, Zoghbi WA, Lakkis NM, Al-Bakshy F, Dhir M, Quinones MA; et al. (2004). "Optimal noninvasive assessment of left ventricular filling pressures: a comparison of tissue Doppler echocardiography and B-type natriuretic peptide in patients with pulmonary artery catheters". Circulation. 109 (20): 2432–9. doi:10.1161/01.CIR.0000127882.58426.7A. PMID 15123522.
↑ Kelder JC, Cowie MR, McDonagh TA, Hardman SM, Grobbee DE, Cost B; et al. (2011). "Quantifying the added value of BNP in suspected heart failure in general practice: an individual patient data meta-analysis". Heart. 97 (12): 959–63. doi:10.1136/hrt.2010.220426. PMID 21478382.
↑ Dokainish H, Zoghbi WA, Lakkis NM, Quinones MA, Nagueh SF (2004). "Comparative accuracy of B-type natriuretic peptide and tissue Doppler echocardiography in the diagnosis of congestive heart failure". Am J Cardiol. 93 (9): 1130–5. doi:10.1016/j.amjcard.2004.01.042. PMID 15110205.
↑ Groenning BA, Raymond I, Hildebrandt PR, Nilsson JC, Baumann M, Pedersen F (2004). "Diagnostic and prognostic evaluation of left ventricular systolic heart failure by plasma N-terminal pro-brain natriuretic peptide concentrations in a large sample of the general population". Heart. 90 (3): 297–303. PMC 1768111. PMID 14966052.
↑ Maisel AS, McCord J, Nowak RM, Hollander JE, Wu AH, Duc P; et al. (2003). "Bedside B-Type natriuretic peptide in the emergency diagnosis of heart failure with reduced or preserved ejection fraction. Results from the Breathing Not Properly Multinational Study". J Am Coll Cardiol. 41 (11): 2010–7. PMID 12798574.
↑ Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL (2013). "2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines". J. Am. Coll. Cardiol. 62 (16): e147–239. doi:10.1016/j.jacc.2013.05.019. PMID 23747642.
↑ Hudson MP, O'Connor CM, Gattis WA, Tasissa G, Hasselblad V, Holleman CM, Gaulden LH, Sedor F, Ohman EM (2004). "Implications of elevated cardiac troponin T in ambulatory patients with heart failure: a prospective analysis". Am. Heart J. 147 (3): 546–52. doi:10.1016/j.ahj.2003.10.014. PMID 14999208.
↑ Horwich TB, Patel J, MacLellan WR, Fonarow GC (2003). "Cardiac troponin I is associated with impaired hemodynamics, progressive left ventricular dysfunction, and increased mortality rates in advanced heart failure". Circulation. 108 (7): 833–8. doi:10.1161/01.CIR.0000084543.79097.34. PMID 12912820.
↑ ^10.0 ^10.1 D'Aloia A, Vizzardi E, Metra M (2016). "Can Carbohydrate Antigen-125 Be a New Biomarker to Guide Heart Failure Treatment?: The CHANCE-HF Trial". JACC Heart Fail. 4 (11): 844–846. doi:10.1016/j.jchf.2016.09.001. PMID 27810078.
↑ ^11.0 ^11.1 Núñez J, Llàcer P, Bertomeu-González V, Bosch MJ, Merlos P, García-Blas S; et al. (2016). "Carbohydrate Antigen-125-Guided Therapy in Acute Heart Failure: CHANCE-HF: A Randomized Study". JACC Heart Fail. 4 (11): 833–843. doi:10.1016/j.jchf.2016.06.007. PMID 27522630.
↑ Nägele H, Bahlo M, Klapdor R, Schaeperkoetter D, Rödiger W (1999). "CA 125 and its relation to cardiac function". Am Heart J. 137 (6): 1044–9. PMID 10347329.
↑ ^13.0 ^13.1 ^13.2 ^13.3 Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW, Antman EM, Smith SC Jr, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B; American College of Cardiology; American Heart Association Task Force on Practice Guidelines; American College of Chest Physicians; International Society for Heart and Lung Transplantation; Heart Rhythm Society. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005 Sep 20; 112(12): e154-235. Epub 2005 Sep 13. PMID 16160202
↑ ^14.0 ^14.1 ^14.2 ^14.3 Jessup M, Abraham WT, Casey DE, Feldman AM, Francis GS, Ganiats TG et al. (2009) 2009 focused update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 119 (14):1977-2016. DOI:10.1161/CIRCULATIONAHA.109.192064 PMID: 19324967
↑ Costello-Boerrigter LC, Boerrigter G, Redfield MM, Rodeheffer RJ, Urban LH, Mahoney DW, Jacobsen SJ, Heublein DM, Burnett JC (2006). "Amino-terminal pro-B-type natriuretic peptide and B-type natriuretic peptide in the general community: determinants and detection of left ventricular dysfunction". J. Am. Coll. Cardiol. 47 (2): 345–53. doi:10.1016/j.jacc.2005.09.025. PMC 2647136. PMID 16412859.
↑ Vasan RS, Benjamin EJ, Larson MG, Leip EP, Wang TJ, Wilson PW, Levy D (2002). "Plasma natriuretic peptides for community screening for left ventricular hypertrophy and systolic dysfunction: the Framingham heart study". JAMA. 288 (10): 1252–9. PMID 12215132.
↑ Januzzi JL, Sakhuja R, O'donoghue M, Baggish AL, Anwaruddin S, Chae CU, Cameron R, Krauser DG, Tung R, Camargo CA, Lloyd-Jones DM (2006). "Utility of amino-terminal pro-brain natriuretic peptide testing for prediction of 1-year mortality in patients with dyspnea treated in the emergency department". Arch. Intern. Med. 166 (3): 315–20. doi:10.1001/archinte.166.3.315. PMID 16476871.
↑ Dao Q, Krishnaswamy P, Kazanegra R, Harrison A, Amirnovin R, Lenert L, Clopton P, Alberto J, Hlavin P, Maisel AS (2001). "Utility of B-type natriuretic peptide in the diagnosis of congestive heart failure in an urgent-care setting". J. Am. Coll. Cardiol. 37 (2): 379–85. PMID 11216950.
↑ ^19.0 ^19.1 van Kimmenade RR, Pinto YM, Bayes-Genis A, Lainchbury JG, Richards AM, Januzzi JL (2006). "Usefulness of intermediate amino-terminal pro-brain natriuretic peptide concentrations for diagnosis and prognosis of acute heart failure". Am. J. Cardiol. 98 (3): 386–90. doi:10.1016/j.amjcard.2006.02.043. PMID 16860029.
↑ ^20.0 ^20.1 ^20.2 Bettencourt P, Azevedo A, Pimenta J, Friões F, Ferreira S, Ferreira A (2004). "N-terminal-pro-brain natriuretic peptide predicts outcome after hospital discharge in heart failure patients". Circulation. 110 (15): 2168–74. doi:10.1161/01.CIR.0000144310.04433.BE. PMID 15451800.
↑ ^21.0 ^21.1 ^21.2 Tang WH, Girod JP, Lee MJ, Starling RC, Young JB, Van Lente F, Francis GS (2003). "Plasma B-type natriuretic peptide levels in ambulatory patients with established chronic symptomatic systolic heart failure". Circulation. 108 (24): 2964–6. doi:10.1161/01.CIR.0000106903.98196.B6. PMID 14662703.
↑ Berger R, Huelsman M, Strecker K, Bojic A, Moser P, Stanek B, Pacher R (2002). "B-type natriuretic peptide predicts sudden death in patients with chronic heart failure". Circulation. 105 (20): 2392–7. PMID 12021226.
↑ Neuhold S, Huelsmann M, Strunk G, Stoiser B, Struck J, Morgenthaler NG, Bergmann A, Moertl D, Berger R, Pacher R (2008). "Comparison of copeptin, B-type natriuretic peptide, and amino-terminal pro-B-type natriuretic peptide in patients with chronic heart failure: prediction of death at different stages of the disease". J. Am. Coll. Cardiol. 52 (4): 266–72. doi:10.1016/j.jacc.2008.03.050. PMID 18634981.
↑ Ledwidge M, Gallagher J, Conlon C, Tallon E, O'Connell E, Dawkins I, Watson C, O'Hanlon R, Bermingham M, Patle A, Badabhagni MR, Murtagh G, Voon V, Tilson L, Barry M, McDonald L, Maurer B, McDonald K (2013). "Natriuretic peptide-based screening and collaborative care for heart failure: the STOP-HF randomized trial". JAMA. 310 (1): 66–74. doi:10.1001/jama.2013.7588. PMID 23821090.
↑ Huelsmann M, Neuhold S, Resl M, Strunk G, Brath H, Francesconi C, Adlbrecht C, Prager R, Luger A, Pacher R, Clodi M (2013). "PONTIAC (NT-proBNP selected prevention of cardiac events in a population of diabetic patients without a history of cardiac disease): a prospective randomized controlled trial". J. Am. Coll. Cardiol. 62 (15): 1365–72. doi:10.1016/j.jacc.2013.05.069. PMID 23810874.
↑ Richards AM, Doughty R, Nicholls MG, MacMahon S, Sharpe N, Murphy J, Espiner EA, Frampton C, Yandle TG (2001). "Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: prognostic utility and prediction of benefit from carvedilol in chronic ischemic left ventricular dysfunction. Australia-New Zealand Heart Failure Group". J. Am. Coll. Cardiol. 37 (7): 1781–7. PMID 11401111.
↑ Zaphiriou A, Robb S, Murray-Thomas T, Mendez G, Fox K, McDonagh T, Hardman SM, Dargie HJ, Cowie MR (2005). "The diagnostic accuracy of plasma BNP and NTproBNP in patients referred from primary care with suspected heart failure: results of the UK natriuretic peptide study". Eur. J. Heart Fail. 7 (4): 537–41. doi:10.1016/j.ejheart.2005.01.022. PMID 15921792.
↑ Anand IS, Fisher LD, Chiang YT, Latini R, Masson S, Maggioni AP, Glazer RD, Tognoni G, Cohn JN (2003). "Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HeFT)". Circulation. 107 (9): 1278–83. PMID 12628948.
↑ ^29.0 ^29.1 Fonarow GC, Peacock WF, Horwich TB, Phillips CO, Givertz MM, Lopatin M, Wynne J (2008). "Usefulness of B-type natriuretic peptide and cardiac troponin levels to predict in-hospital mortality from ADHERE". Am. J. Cardiol. 101 (2): 231–7. doi:10.1016/j.amjcard.2007.07.066. PMID 18178412.
↑ ^30.0 ^30.1 Peacock WF, De Marco T, Fonarow GC, Diercks D, Wynne J, Apple FS, Wu AH (2008). "Cardiac troponin and outcome in acute heart failure". N. Engl. J. Med. 358 (20): 2117–26. doi:10.1056/NEJMoa0706824. PMID 18480204.
↑ Logeart D, Thabut G, Jourdain P, Chavelas C, Beyne P, Beauvais F, Bouvier E, Solal AC (2004). "Predischarge B-type natriuretic peptide assay for identifying patients at high risk of re-admission after decompensated heart failure". J. Am. Coll. Cardiol. 43 (4): 635–41. doi:10.1016/j.jacc.2003.09.044. PMID 14975475.
↑ Dhaliwal AS, Deswal A, Pritchett A, Aguilar D, Kar B, Souchek J, Bozkurt B (2009). "Reduction in BNP levels with treatment of decompensated heart failure and future clinical events". J. Card. Fail. 15 (4): 293–9. doi:10.1016/j.cardfail.2008.11.007. PMID 19398076.
↑ Zairis MN, Tsiaousis GZ, Georgilas AT, Makrygiannis SS, Adamopoulou EN, Handanis SM, Batika PC, Prekates AA, Velissaris D, Kouris NT, Mytas DZ, Babalis DK, Karidis KS, Foussas SG (2010). "Multimarker strategy for the prediction of 31 days cardiac death in patients with acutely decompensated chronic heart failure". Int. J. Cardiol. 141 (3): 284–90. doi:10.1016/j.ijcard.2008.12.017. PMID 19157603.

Template:WikiDoc Sources

[pmid18290826-1] Ewald B, Ewald D, Thakkinstian A, Attia J (2008). "Meta-analysis of B type natriuretic peptide and N-terminal pro B natriuretic peptide in the diagnosis of clinical heart failure and population screening for left ventricular systolic dysfunction". Intern Med J. 38 (2): 101–13. doi:10.1111/j.1445-5994.2007.01454.x. PMID 18290826.

[pmid15123522-2] Dokainish H, Zoghbi WA, Lakkis NM, Al-Bakshy F, Dhir M, Quinones MA; et al. (2004). "Optimal noninvasive assessment of left ventricular filling pressures: a comparison of tissue Doppler echocardiography and B-type natriuretic peptide in patients with pulmonary artery catheters". Circulation. 109 (20): 2432–9. doi:10.1161/01.CIR.0000127882.58426.7A. PMID 15123522.

[pmid21478382-3] Kelder JC, Cowie MR, McDonagh TA, Hardman SM, Grobbee DE, Cost B; et al. (2011). "Quantifying the added value of BNP in suspected heart failure in general practice: an individual patient data meta-analysis". Heart. 97 (12): 959–63. doi:10.1136/hrt.2010.220426. PMID 21478382.

[pmid15110205-4] Dokainish H, Zoghbi WA, Lakkis NM, Quinones MA, Nagueh SF (2004). "Comparative accuracy of B-type natriuretic peptide and tissue Doppler echocardiography in the diagnosis of congestive heart failure". Am J Cardiol. 93 (9): 1130–5. doi:10.1016/j.amjcard.2004.01.042. PMID 15110205.

[pmid14966052-5] Groenning BA, Raymond I, Hildebrandt PR, Nilsson JC, Baumann M, Pedersen F (2004). "Diagnostic and prognostic evaluation of left ventricular systolic heart failure by plasma N-terminal pro-brain natriuretic peptide concentrations in a large sample of the general population". Heart. 90 (3): 297–303. PMC 1768111. PMID 14966052.

[pmid12798574-6] Maisel AS, McCord J, Nowak RM, Hollander JE, Wu AH, Duc P; et al. (2003). "Bedside B-Type natriuretic peptide in the emergency diagnosis of heart failure with reduced or preserved ejection fraction. Results from the Breathing Not Properly Multinational Study". J Am Coll Cardiol. 41 (11): 2010–7. PMID 12798574.

[pmid23747642-7] Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL (2013). "2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines". J. Am. Coll. Cardiol. 62 (16): e147–239. doi:10.1016/j.jacc.2013.05.019. PMID 23747642.

[pmid14999208-8] Hudson MP, O'Connor CM, Gattis WA, Tasissa G, Hasselblad V, Holleman CM, Gaulden LH, Sedor F, Ohman EM (2004). "Implications of elevated cardiac troponin T in ambulatory patients with heart failure: a prospective analysis". Am. Heart J. 147 (3): 546–52. doi:10.1016/j.ahj.2003.10.014. PMID 14999208.

[pmid12912820-9] Horwich TB, Patel J, MacLellan WR, Fonarow GC (2003). "Cardiac troponin I is associated with impaired hemodynamics, progressive left ventricular dysfunction, and increased mortality rates in advanced heart failure". Circulation. 108 (7): 833–8. doi:10.1161/01.CIR.0000084543.79097.34. PMID 12912820.

[pmid27810078-10] 10.0 ^10.1 D'Aloia A, Vizzardi E, Metra M (2016). "Can Carbohydrate Antigen-125 Be a New Biomarker to Guide Heart Failure Treatment?: The CHANCE-HF Trial". JACC Heart Fail. 4 (11): 844–846. doi:10.1016/j.jchf.2016.09.001. PMID 27810078.

[pmid27522630-11] 11.0 ^11.1 Núñez J, Llàcer P, Bertomeu-González V, Bosch MJ, Merlos P, García-Blas S; et al. (2016). "Carbohydrate Antigen-125-Guided Therapy in Acute Heart Failure: CHANCE-HF: A Randomized Study". JACC Heart Fail. 4 (11): 833–843. doi:10.1016/j.jchf.2016.06.007. PMID 27522630.

[pmid10347329-12] Nägele H, Bahlo M, Klapdor R, Schaeperkoetter D, Rödiger W (1999). "CA 125 and its relation to cardiac function". Am Heart J. 137 (6): 1044–9. PMID 10347329.

[Hunt-13] 13.0 ^13.1 ^13.2 ^13.3 Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW, Antman EM, Smith SC Jr, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B; American College of Cardiology; American Heart Association Task Force on Practice Guidelines; American College of Chest Physicians; International Society for Heart and Lung Transplantation; Heart Rhythm Society. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005 Sep 20; 112(12): e154-235. Epub 2005 Sep 13. PMID 16160202

[pmid19324967-14] 14.0 ^14.1 ^14.2 ^14.3 Jessup M, Abraham WT, Casey DE, Feldman AM, Francis GS, Ganiats TG et al. (2009) 2009 focused update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 119 (14):1977-2016. DOI:10.1161/CIRCULATIONAHA.109.192064 PMID: 19324967

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[pmid11216950-18] Dao Q, Krishnaswamy P, Kazanegra R, Harrison A, Amirnovin R, Lenert L, Clopton P, Alberto J, Hlavin P, Maisel AS (2001). "Utility of B-type natriuretic peptide in the diagnosis of congestive heart failure in an urgent-care setting". J. Am. Coll. Cardiol. 37 (2): 379–85. PMID 11216950.

[pmid16860029-19] 19.0 ^19.1 van Kimmenade RR, Pinto YM, Bayes-Genis A, Lainchbury JG, Richards AM, Januzzi JL (2006). "Usefulness of intermediate amino-terminal pro-brain natriuretic peptide concentrations for diagnosis and prognosis of acute heart failure". Am. J. Cardiol. 98 (3): 386–90. doi:10.1016/j.amjcard.2006.02.043. PMID 16860029.

[pmid15451800-20] 20.0 ^20.1 ^20.2 Bettencourt P, Azevedo A, Pimenta J, Friões F, Ferreira S, Ferreira A (2004). "N-terminal-pro-brain natriuretic peptide predicts outcome after hospital discharge in heart failure patients". Circulation. 110 (15): 2168–74. doi:10.1161/01.CIR.0000144310.04433.BE. PMID 15451800.

[pmid14662703-21] 21.0 ^21.1 ^21.2 Tang WH, Girod JP, Lee MJ, Starling RC, Young JB, Van Lente F, Francis GS (2003). "Plasma B-type natriuretic peptide levels in ambulatory patients with established chronic symptomatic systolic heart failure". Circulation. 108 (24): 2964–6. doi:10.1161/01.CIR.0000106903.98196.B6. PMID 14662703.

[pmid12021226-22] Berger R, Huelsman M, Strecker K, Bojic A, Moser P, Stanek B, Pacher R (2002). "B-type natriuretic peptide predicts sudden death in patients with chronic heart failure". Circulation. 105 (20): 2392–7. PMID 12021226.

[pmid18634981-23] Neuhold S, Huelsmann M, Strunk G, Stoiser B, Struck J, Morgenthaler NG, Bergmann A, Moertl D, Berger R, Pacher R (2008). "Comparison of copeptin, B-type natriuretic peptide, and amino-terminal pro-B-type natriuretic peptide in patients with chronic heart failure: prediction of death at different stages of the disease". J. Am. Coll. Cardiol. 52 (4): 266–72. doi:10.1016/j.jacc.2008.03.050. PMID 18634981.

[pmid23821090-24] Ledwidge M, Gallagher J, Conlon C, Tallon E, O'Connell E, Dawkins I, Watson C, O'Hanlon R, Bermingham M, Patle A, Badabhagni MR, Murtagh G, Voon V, Tilson L, Barry M, McDonald L, Maurer B, McDonald K (2013). "Natriuretic peptide-based screening and collaborative care for heart failure: the STOP-HF randomized trial". JAMA. 310 (1): 66–74. doi:10.1001/jama.2013.7588. PMID 23821090.

[pmid23810874-25] Huelsmann M, Neuhold S, Resl M, Strunk G, Brath H, Francesconi C, Adlbrecht C, Prager R, Luger A, Pacher R, Clodi M (2013). "PONTIAC (NT-proBNP selected prevention of cardiac events in a population of diabetic patients without a history of cardiac disease): a prospective randomized controlled trial". J. Am. Coll. Cardiol. 62 (15): 1365–72. doi:10.1016/j.jacc.2013.05.069. PMID 23810874.

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@@ Line 23: / Line 23: @@
 ==Biomarkers==
-Biomarkers are going to play a great role in diagnosis of heart failure. In addition to routine laboratory tests, they are gaining attention in heart failure management.
+Biomarkers are going to play a great role in diagnosis of heart failure.
 ===Natriuretic Peptides: BNP or NT-proBNP===
-BNP or its amino-terminal cleavage equivalent (NT-proBNP) is generated by cardiomyocytes in the context of numerous triggers, most notably myocardial stretch.
+BNP or its amino-terminal cleavage equivalent (NT-proBNP) is generated by cardiomyocytes in the context of numerous triggers, most notably myocardial stretch. These biomarkers have been studied for the detection of elevated cardiac pressured<ref name="pmid15123522">{{cite journal| author=Dokainish H, Zoghbi WA, Lakkis NM, Al-Bakshy F, Dhir M, Quinones MA et al.| title=Optimal noninvasive assessment of left ventricular filling pressures: a comparison of tissue Doppler echocardiography and B-type natriuretic peptide in patients with pulmonary artery catheters. | journal=Circulation | year= 2004 | volume= 109 | issue= 20 | pages= 2432-9 | pmid=15123522 | doi=10.1161/01.CIR.0000127882.58426.7A | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15123522  }} </ref><ref name="pmid21478382">{{cite journal| author=Kelder JC, Cowie MR, McDonagh TA, Hardman SM, Grobbee DE, Cost B et al.| title=Quantifying the added value of BNP in suspected heart failure in general practice: an individual patient data meta-analysis. | journal=Heart | year= 2011 | volume= 97 | issue= 12 | pages= 959-63 | pmid=21478382 | doi=10.1136/hrt.2010.220426 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21478382  }} </ref><ref name="pmid15110205">{{cite journal| author=Dokainish H, Zoghbi WA, Lakkis NM, Quinones MA, Nagueh SF| title=Comparative accuracy of B-type natriuretic peptide and tissue Doppler echocardiography in the diagnosis of congestive heart failure. | journal=Am J Cardiol | year= 2004 | volume= 93 | issue= 9 | pages= 1130-5 | pmid=15110205 | doi=10.1016/j.amjcard.2004.01.042 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15110205  }} </ref>, low ejection fraction<ref name="pmid14966052">{{cite journal| author=Groenning BA, Raymond I, Hildebrandt PR, Nilsson JC, Baumann M, Pedersen F| title=Diagnostic and prognostic evaluation of left ventricular systolic heart failure by plasma N-terminal pro-brain natriuretic peptide concentrations in a large sample of the general population. | journal=Heart | year= 2004 | volume= 90 | issue= 3 | pages= 297-303 | pmid=14966052 | doi= | pmc=1768111 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14966052  }} </ref>, or both<ref name="pmid12798574">{{cite journal| author=Maisel AS, McCord J, Nowak RM, Hollander JE, Wu AH, Duc P et al.| title=Bedside B-Type natriuretic peptide in the emergency diagnosis of heart failure with reduced or preserved ejection fraction. Results from the Breathing Not Properly Multinational Study. | journal=J Am Coll Cardiol | year= 2003 | volume= 41 | issue= 11 | pages= 2010-7 | pmid=12798574 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12798574  }} </ref>.
-Their measurement is helpful for diagnosis or ruling out heart failure especially in acute setting.<ref name="pmid23747642">{{cite journal |vauthors=Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL |title=2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines |journal=J. Am. Coll. Cardiol. |volume=62 |issue=16 |pages=e147–239 |year=2013 |pmid=23747642 |doi=10.1016/j.jacc.2013.05.019 |url=}}</ref>
+[[Clinical practice guideline]]s suggest their measurement is helpful for diagnosis or ruling out heart failure especially in acute setting.<ref name="pmid23747642">{{cite journal |vauthors=Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL |title=2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines |journal=J. Am. Coll. Cardiol. |volume=62 |issue=16 |pages=e147–239 |year=2013 |pmid=23747642 |doi=10.1016/j.jacc.2013.05.019 |url=}}</ref>
 {| class="wikitable"
@@ Line 69: / Line 72: @@
 === Carbohydrate Antigen 125 ===
-CA-125 is an emerging, highly sensitive biomarker for heart failure.<ref name="pmid27810078">{{cite journal| author=D'Aloia A, Vizzardi E, Metra M| title=Can Carbohydrate Antigen-125 Be a New Biomarker to Guide Heart Failure Treatment?: The CHANCE-HF Trial. | journal=JACC Heart Fail | year= 2016 | volume= 4 | issue= 11 | pages= 844-846 | pmid=27810078 | doi=10.1016/j.jchf.2016.09.001 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27810078  }} </ref> Although it is not yet used in clinical practice, the CHANCE-HF trial has demonstrated utility in using CA-125 to guide diuretic therapy and for determining short-term prognosis.<ref name="pmid27522630">{{cite journal| author=Núñez J, Llàcer P, Bertomeu-González V, Bosch MJ, Merlos P, García-Blas S et al.| title=Carbohydrate Antigen-125-Guided Therapy in Acute Heart Failure: CHANCE-HF: A Randomized Study. | journal=JACC Heart Fail | year= 2016 | volume= 4 | issue= 11 | pages= 833-843 | pmid=27522630 | doi=10.1016/j.jchf.2016.06.007 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27522630  }} </ref> CA-125 is a non-specific antigen that is most strongly associated with ovarian cancer. In patients with acute heart failure, ambulatory follow-up care aimed at titrating diuretic use according to CA-125 levels has demonstrated ~50% reduction in rehospitalizations.<ref name="pmid27522630">{{cite journal| author=Núñez J, Llàcer P, Bertomeu-González V, Bosch MJ, Merlos P, García-Blas S et al.| title=Carbohydrate Antigen-125-Guided Therapy in Acute Heart Failure: CHANCE-HF: A Randomized Study. | journal=JACC Heart Fail | year= 2016 | volume= 4 | issue= 11 | pages= 833-843 | pmid=27522630 | doi=10.1016/j.jchf.2016.06.007 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27522630  }} </ref> CA-125 was first associated with heart failure in 1999 by Nagele et al.<ref name="pmid27810078">{{cite journal| author=D'Aloia A, Vizzardi E, Metra M| title=Can Carbohydrate Antigen-125 Be a New Biomarker to Guide Heart Failure Treatment?: The CHANCE-HF Trial. | journal=JACC Heart Fail | year= 2016 | volume= 4 | issue= 11 | pages= 844-846 | pmid=27810078 | doi=10.1016/j.jchf.2016.09.001 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27810078  }} </ref><ref name="pmid10347329">{{cite journal| author=Nägele H, Bahlo M, Klapdor R, Schaeperkoetter D, Rödiger W| title=CA 125 and its relation to cardiac function. | journal=Am Heart J | year= 1999 | volume= 137 | issue= 6 | pages= 1044-9 | pmid=10347329 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10347329  }} </ref>
+CA-125 is an emerging, highly sensitive biomarker for heart failure.<ref name="pmid27810078">{{cite journal| author=D'Aloia A, Vizzardi E, Metra M| title=Can Carbohydrate Antigen-125 Be&nbsp;a&nbsp;New&nbsp;Biomarker to Guide Heart&nbsp;Failure&nbsp;Treatment?: The CHANCE-HF Trial. | journal=JACC Heart Fail | year= 2016 | volume= 4 | issue= 11 | pages= 844-846 | pmid=27810078 | doi=10.1016/j.jchf.2016.09.001 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27810078  }} </ref> Although it is not yet used in clinical practice, the CHANCE-HF trial has demonstrated utility in using CA-125 to guide diuretic therapy and for determining short-term prognosis.<ref name="pmid27522630">{{cite journal| author=Núñez J, Llàcer P, Bertomeu-González V, Bosch MJ, Merlos P, García-Blas S et al.| title=Carbohydrate Antigen-125-Guided Therapy in Acute Heart Failure: CHANCE-HF: A Randomized Study. | journal=JACC Heart Fail | year= 2016 | volume= 4 | issue= 11 | pages= 833-843 | pmid=27522630 | doi=10.1016/j.jchf.2016.06.007 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27522630  }} </ref> CA-125 is a non-specific antigen that is most strongly associated with ovarian cancer. In patients with acute heart failure, ambulatory follow-up care aimed at titrating diuretic use according to CA-125 levels has demonstrated ~50% reduction in rehospitalizations.<ref name="pmid27522630">{{cite journal| author=Núñez J, Llàcer P, Bertomeu-González V, Bosch MJ, Merlos P, García-Blas S et al.| title=Carbohydrate Antigen-125-Guided Therapy in Acute Heart Failure: CHANCE-HF: A Randomized Study. | journal=JACC Heart Fail | year= 2016 | volume= 4 | issue= 11 | pages= 833-843 | pmid=27522630 | doi=10.1016/j.jchf.2016.06.007 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27522630  }} </ref> CA-125 was first associated with heart failure in 1999 by Nagele et al.<ref name="pmid27810078">{{cite journal| author=D'Aloia A, Vizzardi E, Metra M| title=Can Carbohydrate Antigen-125 Be&nbsp;a&nbsp;New&nbsp;Biomarker to Guide Heart&nbsp;Failure&nbsp;Treatment?: The CHANCE-HF Trial. | journal=JACC Heart Fail | year= 2016 | volume= 4 | issue= 11 | pages= 844-846 | pmid=27810078 | doi=10.1016/j.jchf.2016.09.001 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27810078  }} </ref><ref name="pmid10347329">{{cite journal| author=Nägele H, Bahlo M, Klapdor R, Schaeperkoetter D, Rödiger W| title=CA 125 and its relation to cardiac function. | journal=Am Heart J | year= 1999 | volume= 137 | issue= 6 | pages= 1044-9 | pmid=10347329 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10347329  }} </ref>
 ==2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure/2013 ACCF/AHA Guideline for the Management of Heart Failure/2009 ACC/AHA Focused Update and 2005 Guidelines for the Diagnosis and Management of Chronic Heart Failure in the Adult (DO NOT EDIT)<ref name="Hunt"> Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW, Antman EM, Smith SC Jr, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B; American College of Cardiology; American Heart Association Task Force on Practice Guidelines; American College of Chest Physicians; International Society for Heart and Lung Transplantation; Heart Rhythm Society. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005 Sep 20; 112(12): e154-235. Epub 2005 Sep 13. PMID 16160202</ref><ref name="pmid19324967">Jessup M, Abraham WT, Casey DE, Feldman AM, Francis GS, Ganiats TG et al. (2009) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=19324967 2009 focused update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation.] ''Circulation'' 119 (14):1977-2016. [http://dx.doi.org/10.1161/CIRCULATIONAHA.109.192064 DOI:10.1161/CIRCULATIONAHA.109.192064] PMID: [http://pubmed.gov/19324967 19324967]</ref>==