Congestive heart failure with preserved EF pharmacotherapy: Difference between revisions
Jump to navigation
Jump to search
(/* 2021 European Society of Cardiology Guidelines (DO NOT EDIT) {{cite journal |vauthors=McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, Burri H, Butler J, Čelutkienė J, Chioncel O, Cleland JGF, Coats AJS, Crespo-Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam CSP, Lyon AR, McMurray JJV, Mebazaa A, Mindham R, Muneretto C, Francesco Piepoli M, Price S, Rosano GMC, Ruschitzka F, Kathrine Skibelund A |title=2021 ESC Guidelines for the d...) |
(/* 2022 AHA/ACC/HFSA Heart Failure Guideline (DO NOT EDIT) {{cite journal| author=Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM | display-authors=etal| title=2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. | journal=Circulation | year= 2022 | volume= 145 | issue= 18 | pages= e876-e894 | pmid=35363500 | doi=10.1161/C...) |
||
| Line 113: | Line 113: | ||
|} | |} | ||
== 2022 AHA/ACC/HFSA Heart Failure Guideline (DO NOT EDIT) <ref name="pmid35363500">{{cite journal| author=Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM | display-authors=etal| title=2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. | journal=Circulation | year= 2022 | volume= 145 | issue= 18 | pages= e876-e894 | pmid=35363500 | doi=10.1161/CIR.0000000000001062 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=35363500 }} </ref>=== | === 2022 AHA/ACC/HFSA Heart Failure Guideline (DO NOT EDIT) <ref name="pmid35363500">{{cite journal| author=Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM | display-authors=etal| title=2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. | journal=Circulation | year= 2022 | volume= 145 | issue= 18 | pages= e876-e894 | pmid=35363500 | doi=10.1161/CIR.0000000000001062 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=35363500 }} </ref>==== | ||
===[[Treatment]] of [[Patients]] with [[HF]] and preserved ejection fraction [[diastolic dysfunction|HFpEF]] (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>=== | ====[[Treatment]] of [[Patients]] with [[HF]] and preserved ejection fraction [[diastolic dysfunction|HFpEF]] (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>==== | ||
====[[HF]] With Preserved [[Ejection Fraction]]==== | =====[[HF]] With Preserved [[Ejection Fraction]]===== | ||
{|class="wikitable" style="width:80%" | {|class="wikitable" style="width:80%" | ||
Revision as of 20:15, 22 June 2022
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Sara Zand, M.D.[2] Seyedmahdi Pahlavani, M.D. [3]
Overview
Heart failure has been divided into three subgroups including heart failure reduced ejection fraction, heart failure mildly reduced EF, heart failure preserved EF. HFrEF is defined when LVEF≤ 40% and significant LV systolic dysfunction. Patients with a LVEF between 41% and 49% have mildly reduced LV systolic function or HFmrEF. Patients with ejection fractions between 40-50% may benefit from similar therapies to those with LVEF≤ 40%. HFpEF is explained in the presence of symptoms and signs of HF, and evidence of structural and/or functional cardiac abnormalities and/or raised natriuretic peptides (NPs), and LVEF≥ 50%. Patients with non-cardiovascular disease including anaemia, pulmonary, renal, thyroid, or hepatic disease may mimic symptoms and signs of HF, but in the absence of cardiac dysfunction, they are not diagnosed for HF. Neverthless, these disorders can coexist with HF and exacerbate the HF syndrome.
Heart failure mildly reduced ejection fraction (HPmrEF), EF (41-49%)
The diagnosis of heart failure with mildly reduced ejection fraction
- The diagnosis of HFmrEF requires the presence of symptoms and/or signs of HF, and a mildly reduced EF (41-49%) The presence of elevated NPs (BNP ≥35 pg/mL or NT-proBNP ≥125 pg/mL) and other evidence of structural heart disease including increased left atrial (LA) size, LVH or echocardiographic measures of LV filling.[1]
Clinical characteristics
- Clinical characteristics, risk factors, patterns of cardiac remodelling are similar to other subgroups of HF.
- HFmrEF is more common in men, younger, and are more likely to have CAD (50-60%) and less likely to have AF and non-cardiac comorbidities. ambulatory
- HFmrEF have lower mortality rate than those with HFrEF.
Treatment
Angiotensin-converting enzyme inhibitors
- ACE-I may be considered in patients with HFmrEF and underlying CAD, hypertension, or post-MI LV systolic dysfunction.
Angiotensin receptor II type 1 receptor blockers
- Candesartan reduced the number of patients hospitalized for HF among those with HFmrEF.[2]
- Treatment with ARBs may be considered in patients with HFmrEF patients with other cardiovascular indications.
Beta-blockers
- Treatment with beta-blockers may be considered in patients with HFmrEF and another cardiovascular indications, such as AF or angina.[3]
Mineralocorticoid receptor antagonists
- In a retrospective analysis of the TOPCAT trial in patients with LVEF ≥45%, spironolactone reduced hospitalizations for HF in patients with an LVEF <55%.
- Treatment with an MRA may be considered in patients with HFmrEF.
Angiotensin receptor-neprilysin inhibitor
- Analysis of the PARADIGM-HF and PARAGON-HF trials showed that sacubitril/valsartan, compared to other forms of RAAS blockade reduced hospitalizations in patients with HFmrEF.
Other drugs
- In the DIG trial, use of digoxin for patients with HFmrEF in sinus rhythm was associated with fewer hospitalizations but no reduction in mortality and a trend to increase of cardiovascular deaths.
- Therefore, there are insufficient data to recommend its use.
- There are insufficient data on ivabradine in HFmrEF.
Devices
2021 European Society of Cardiology Guidelines (DO NOT EDIT) [4]
Medications indicated in patients with New York Heart Association (NYHA class II–IV) HFmrEF (heart failure with mildly reduced ejection fraction) (LVEF41-49%)
| Recommedation for patients with NYHA class 2-4 heart failure with mildly reduced ejection fraction |
| Diuretics (Class I, Level of Evidence C): |
|
❑ Diuretics are recommended in patients with congestion and HFmrEF in order reduce symptoms and signs |
| ACEI (Class IIb, Level of Evidence C): |
|
❑ ACE-I may be considered for patients with HFmrEF to reduce the risk of HF hospitalization and death |
Heart failure preserved ejection fraction (HFpEF)
Clinical characteristics
- HFpEF patients are older and more often female.
- AF, CKD, and non-cardiovascular comorbidities are more common in patients with HFpEF.[5]
- It is important to exclude other conditions that might mimic the HFpEF syndrome including lung disease, anaemia, obesity, and deconditioning.
The diagnosis of heart failure preserved ejection fraction
- Echocardiographic criteria:
- LA size (LA volume index >32 mL/m2)
- Mitral E velocity <90 cm/s
- Septal e' velocity <9 cm/s
- E/e' ratio >9
- The diagnosis is made when there are the following:
(1) Symptoms and signs of HF
(2) An LVEF ≥ 50%
(3) Evidence of cardiac structural and/or functional abnormalities consistent with the presence of LV diastolic dysfunction/ raised LV filling pressures, including raised NPs
- In the presence of AF, the threshold for LA volume index is >40 mL/m2
- Exercise stress thresholds include E/e' ratio at peak stress ≥ 15 or tricuspid regurgitation (TR) velocity at peak stress >3.4 m/s
- LV global longitudinal strain <16%
- An invasively measured pulmonary capillary wedge pressure (PCWP) of ≥15 mmHg (at rest) or ≥25 mmHg (with exercise) or LV end-diastolic pressure ≥16 mmHg (at rest) is generally considered diagnostic.[6]
- In the presence of non-invasive markers of raised LV filling pressures, the probability of a diagnosis of HFpEF increases.[7]
- No treatment has been shown to reduce mortality and morbidity in patients with HFpEF.
- Hospitalizations for HF were reduced by candesartan and spironolactone, sacubitril/valsartan.
- Many of HFpEF patients have underlying hypertension and/or CAD, treated with ACE-I/ARB, beta-blockers, or MRAs.
- The Food and Drug Administration (FDA) has confirmed the use of sacubitril/valsartan and spironolactone in those with an LVEF ‘less than normal’.
- These statements relate to patients within both the HFmrEF and HFpEF categories.
- For sacubitril/valsartan, subgroup analysis from the PARAGON-HF study showed a reduction in HF hospitalizations in patients with LVEF <57%, and a meta-analysis of the PARADIGM-HF and PARAGON-HF studies showed a reduction in cardiovascular death and HF hospitalization in patients with LVEF below the normal range.
- Use of spironolactone, in TOPCAT study was associated with reduced cardiovascular death and HF hospitalization,
- Treatment should be aimed at reducing symptoms of congestion with diuretics such as loop diuretic.
- Thiazide diuretics may be useful for managing hypertension.
- Reducing body weight in obese patients and increasing exercise may further improve symptoms and exercise capacity.
- Notably in patients with HFpEF, treatment of underlying risk factors, etiology, and coexisting comorbidities such as hypertension, CAD, AF, valvular heart disease are recommended.
2021 European Society of Cardiology Guidelines (DO NOT EDIT) [4]
| Recommedation for treatment of patients with HFpEF (heart failure preserved ejection fraction) |
| (Class I, Level of Evidence C): |
|
❑ Screening, treatment, investigation about underlying etiologies, and
cardiovascular and non-cardiovascular comorbidities is recommended in patients with HFpEF |
2022 AHA/ACC/HFSA Heart Failure Guideline (DO NOT EDIT) [8]=
Treatment of Patients with HF and preserved ejection fraction HFpEF (DO NOT EDIT) [9]
HF With Preserved Ejection Fraction
| Class I |
| "1. Patients with HFpEF and hypertension should have medication titrated to attain blood pressure targets in accordance with published clinical practice guidelines to prevent morbidity. [10][11][12] (Level of Evidence: C-LD) " |
| Class IIa |
| "2. In patients with HFpEF, SGLT2i can be beneficial in decreasing HF hospitalizations and cardiovascular mortality. [13] (Level of Evidence:B-R) " |
| "3. In patients with HFpEF, management of AF can be useful to improve symptoms. (Level of Evidence: C-EO) " |
| Class IIb |
| "4. In selected patients with HFpEF, MRAs may be considered to decrease hospitalizations, particularly among patients with LVEF on the lower end of this spectrum. [14][15][16] (Level of Evidence:B-R) " |
| "5. In selected patients with HFpEF, the use of ARB may be considered to decrease hospitalizations, particularly among patients with LVEF on the lower end of this spectrum. [2][17](Level of Evidence: B-R) " |
| "6. In selected patients with HFpEF, ARNi may be considered to decrease hospitalizations, particularly among patients with LVEF on the lower end of this spectrum. [18][19](Level of Evidence: B-R) " |
| Class III (No Benefit) |
| "7. In patients with HFpEF, routine use of nitrates or phosphodiesterase-5 inhibitors to increase activity or QOL is ineffective. [20][21] (Level of Evidence:B-R) " |
References
- ↑ Tsuji K, Sakata Y, Nochioka K, Miura M, Yamauchi T, Onose T, Abe R, Oikawa T, Kasahara S, Sato M, Shiroto T, Takahashi J, Miyata S, Shimokawa H (October 2017). "Characterization of heart failure patients with mid-range left ventricular ejection fraction-a report from the CHART-2 Study". Eur J Heart Fail. 19 (10): 1258–1269. doi:10.1002/ejhf.807. PMID 28370829.
- ↑ 2.0 2.1 Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J (September 2003). "Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial". Lancet. 362 (9386): 777–81. doi:10.1016/S0140-6736(03)14285-7. PMID 13678871.
- ↑ Flather MD, Shibata MC, Coats AJ, Van Veldhuisen DJ, Parkhomenko A, Borbola J, Cohen-Solal A, Dumitrascu D, Ferrari R, Lechat P, Soler-Soler J, Tavazzi L, Spinarova L, Toman J, Böhm M, Anker SD, Thompson SG, Poole-Wilson PA (February 2005). "Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS)". Eur Heart J. 26 (3): 215–25. doi:10.1093/eurheartj/ehi115. PMID 15642700.
- ↑ 4.0 4.1 McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, Burri H, Butler J, Čelutkienė J, Chioncel O, Cleland J, Coats A, Crespo-Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam C, Lyon AR, McMurray J, Mebazaa A, Mindham R, Muneretto C, Francesco Piepoli M, Price S, Rosano G, Ruschitzka F, Kathrine Skibelund A (September 2021). "2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure". Eur Heart J. 42 (36): 3599–3726. doi:10.1093/eurheartj/ehab368. PMID 34447992 Check
|pmid=value (help). Vancouver style error: initials (help) - ↑ Borlaug BA (September 2020). "Evaluation and management of heart failure with preserved ejection fraction". Nat Rev Cardiol. 17 (9): 559–573. doi:10.1038/s41569-020-0363-2. PMID 32231333 Check
|pmid=value (help). - ↑ Barandiarán Aizpurua A, Sanders-van Wijk S, Brunner-La Rocca HP, Henkens M, Heymans S, Beussink-Nelson L, Shah SJ, van Empel V (March 2020). "Validation of the HFA-PEFF score for the diagnosis of heart failure with preserved ejection fraction". Eur J Heart Fail. 22 (3): 413–421. doi:10.1002/ejhf.1614. PMID 31472035. Vancouver style error: initials (help)
- ↑ Ho JE, Zern EK, Wooster L, Bailey CS, Cunningham T, Eisman AS, Hardin KM, Zampierollo GA, Jarolim P, Pappagianopoulos PP, Malhotra R, Nayor M, Lewis GD (July 2019). "Differential Clinical Profiles, Exercise Responses, and Outcomes Associated With Existing HFpEF Definitions". Circulation. 140 (5): 353–365. doi:10.1161/CIRCULATIONAHA.118.039136. PMID 31132875.
- ↑ Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM; et al. (2022). "2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines". Circulation. 145 (18): e876–e894. doi:10.1161/CIR.0000000000001062. PMID 35363500 Check
|pmid=value (help). - ↑ 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
- ↑ Thomopoulos C, Parati G, Zanchetti A (2016). "Effects of blood-pressure-lowering treatment in hypertension: 9. Discontinuations for adverse events attributed to different classes of antihypertensive drugs: meta-analyses of randomized trials". J Hypertens. 34 (10): 1921–32. doi:10.1097/HJH.0000000000001052. PMID 27454050.
- ↑ Williamson JD, Supiano MA, Applegate WB, Berlowitz DR, Campbell RC, Chertow GM; et al. (2016). "Intensive vs Standard Blood Pressure Control and Cardiovascular Disease Outcomes in Adults Aged ≥75 Years: A Randomized Clinical Trial". JAMA. 315 (24): 2673–82. doi:10.1001/jama.2016.7050. PMC 4988796. PMID 27195814. Review in: Ann Intern Med. 2016 Aug 16;165(4):JC14 Review in: Evid Based Med. 2017 Mar;22(1):30
- ↑ SPRINT Research Group. Wright JT, Williamson JD, Whelton PK, Snyder JK, Sink KM; et al. (2015). "A Randomized Trial of Intensive versus Standard Blood-Pressure Control". N Engl J Med. 373 (22): 2103–16. doi:10.1056/NEJMoa1511939. PMC 4689591. PMID 26551272. Review in: Ann Intern Med. 2016 Feb 16;164(4):JC15 Review in: Evid Based Med. 2016 Jun;21(3):101
- ↑ Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Böhm M; et al. (2021). "Empagliflozin in Heart Failure with a Preserved Ejection Fraction". N Engl J Med. 385 (16): 1451–1461. doi:10.1056/NEJMoa2107038. PMID 34449189 Check
|pmid=value (help). Review in: Ann Intern Med. 2022 Jan;175(1):JC4 - ↑ Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B; et al. (2014). "Spironolactone for heart failure with preserved ejection fraction". N Engl J Med. 370 (15): 1383–92. doi:10.1056/NEJMoa1313731. PMID 24716680. Review in: Ann Intern Med. 2014 Oct 21;161(8):JC6
- ↑ Pfeffer MA, Claggett B, Assmann SF, Boineau R, Anand IS, Clausell N; et al. (2015). "Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial". Circulation. 131 (1): 34–42. doi:10.1161/CIRCULATIONAHA.114.013255. PMID 25406305.
- ↑ Solomon SD, Claggett B, Desai AS, Packer M, Zile M, Swedberg K; et al. (2016). "Influence of Ejection Fraction on Outcomes and Efficacy of Sacubitril/Valsartan (LCZ696) in Heart Failure with Reduced Ejection Fraction: The Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) Trial". Circ Heart Fail. 9 (3): e002744. doi:10.1161/CIRCHEARTFAILURE.115.002744. PMID 26915374.
- ↑ Lund LH, Claggett B, Liu J, Lam CS, Jhund PS, Rosano GM; et al. (2018). "Heart failure with mid-range ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire ejection fraction spectrum". Eur J Heart Fail. 20 (8): 1230–1239. doi:10.1002/ejhf.1149. PMID 29431256.
- ↑ Solomon SD, McMurray JJV, Anand IS, Ge J, Lam CSP, Maggioni AP; et al. (2019). "Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction". N Engl J Med. 381 (17): 1609–1620. doi:10.1056/NEJMoa1908655. PMID 31475794.
- ↑ Solomon SD, Vaduganathan M, L Claggett B, Packer M, Zile M, Swedberg K; et al. (2020). "Sacubitril/Valsartan Across the Spectrum of Ejection Fraction in Heart Failure". Circulation. 141 (5): 352–361. doi:10.1161/CIRCULATIONAHA.119.044586. PMID 31736342. Review in: Ann Intern Med. 2020 Jun 16;172(12):JC65
- ↑ Redfield MM, Anstrom KJ, Levine JA, Koepp GA, Borlaug BA, Chen HH; et al. (2015). "Isosorbide Mononitrate in Heart Failure with Preserved Ejection Fraction". N Engl J Med. 373 (24): 2314–24. doi:10.1056/NEJMoa1510774. PMC 4712067. PMID 26549714.
- ↑ Redfield MM, Chen HH, Borlaug BA, Semigran MJ, Lee KL, Lewis G; et al. (2013). "Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial". JAMA. 309 (12): 1268–77. doi:10.1001/jama.2013.2024. PMC 3835156. PMID 23478662.