Congestive heart failure with reduced EF

Jump to navigation Jump to search
Congestive Heart Failure Microchapters


Patient Information


Historical Perspective



Systolic Dysfunction
Diastolic Dysfunction


Differentiating Congestive heart failure from other Diseases

Epidemiology and Demographics

Risk Factors


Natural History, Complications and Prognosis


Clinical Assessment

History and Symptoms

Physical Examination

Laboratory Findings


Chest X Ray

Cardiac MRI


Exercise Stress Test

Myocardial Viability Studies

Cardiac Catheterization

Other Imaging Studies

Other Diagnostic Studies


Invasive Hemodynamic Monitoring

Medical Therapy:

Acute Pharmacotherapy
Chronic Pharmacotherapy in HFpEF
Chronic Pharmacotherapy in HFrEF
ACE Inhibitors
Angiotensin receptor blockers
Aldosterone Antagonists
Beta Blockers
Ca Channel Blockers
Positive Inotropics
Angiotensin Receptor-Neprilysin Inhibitor
Antiarrhythmic Drugs
Nutritional Supplements
Hormonal Therapies
Drugs to Avoid
Drug Interactions
Treatment of underlying causes
Associated conditions

Exercise Training

Surgical Therapy:

Biventricular Pacing or Cardiac Resynchronization Therapy (CRT)
Implantation of Intracardiac Defibrillator
Cardiac Surgery
Left Ventricular Assist Devices (LVADs)
Cardiac Transplantation

ACC/AHA Guideline Recommendations

Initial and Serial Evaluation of the HF Patient
Hospitalized Patient
Patients With a Prior MI
Sudden Cardiac Death Prevention
Surgical/Percutaneous/Transcather Interventional Treatments of HF
Patients at high risk for developing heart failure (Stage A)
Patients with cardiac structural abnormalities or remodeling who have not developed heart failure symptoms (Stage B)
Patients with current or prior symptoms of heart failure (Stage C)
Patients with refractory end-stage heart failure (Stage D)
Coordinating Care for Patients With Chronic HF
Quality Metrics/Performance Measures

Implementation of Practice Guidelines

Congestive heart failure end-of-life considerations

Specific Groups:

Special Populations
Patients who have concomitant disorders
Obstructive Sleep Apnea in the Patient with CHF
NSTEMI with Heart Failure and Cardiogenic Shock

Congestive heart failure with reduced EF On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides


Ongoing Trials at Clinical

US National Guidelines Clearinghouse

NICE Guidance

FDA on Congestive heart failure with reduced EF

CDC on Congestive heart failure with reduced EF

Congestive heart failure with reduced EF in the news

Blogs on Congestive heart failure with reduced EF

Directions to Hospitals Treating Congestive heart failure with reduced EF

Risk calculators and risk factors for Congestive heart failure with reduced EF

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]


The pathogenesis of HFrEF is related largely to cellular proliferation and metabolism. Pathological processes that result in progression of HF and are common to both HFrEF and HFpEF are altered excitation-contraction coupling, epigenetic modifications, changes in sarcomeric coupling proteins, increased adrenergic drive, increased activity of renin-angiotensin aldosterone axis, nitric oxide insensitivity, adenosine triphosphate (ATP) depletion, reactive oxygen species production and an elevated cell death rate.

Heart Failure With Reduced Ejection Fraction (HFrEF)

The pathogenesis of HFrEF is related largely to cellular proliferation and metabolism. Pathological processes that result in progression of HF and are common to both HFrEF and HFpEF are altered excitation-contraction coupling, epigenetic modifications, changes in sarcomeric coupling proteins, increased adrenergic drive, increased activity of renin-angiotensin aldosterone axis, nitric oxide insensitivity, adenosine triphosphate (ATP) depletion, reactive oxygen species production and an elevated cell death rate.

Precipitating factors

Increased adrenergic drive

Renin-angiotensin aldosterone pathway

Impact on the Frank Starling curve

Counter-balancing factors to increased adrenergic drive

Dysregulated excitation-contraction coupling

Cardiac remodeling

Activation of DNA binding transcription factors

  • It has been proposed that dysregulation in epigenetic signals, cellular messengers and molecular targets precedes pathological cardiac remodeling, disrupts progenitor cell functions, adversely affects the endogenous repair system, and metabolic pathways.
  • Hypoxia-inducible factor 1 (HIF-1) has been shown to be upregulated in HFrEF. This trasnscription activator is involved in various oxidation-reduction reactions, angiogenesis and vascular remodelling. Myocardial hypoxia leads to its activation which downstream produces elevated levels of brain natriuretic peptide (BNP). Hypoperfusion of peripheral organs leading to hypoxia is the key trigger for induction of increased HIF-1 activity.[26][26][27]
  • DNA methylation, histone modification and ATP-dependent chromatin remodelling all lead to epigenetic signature changes and reprogramming of of gene expression. DNA methylation is under the control of HIF-1, angiomotin-like 2, and Rho GTPase activating protein 24 which are under the influence of cardiac fibroblasts suffering from hypoxia.[28][29]
  • These processes ultimately down-regulate alpha-myosin heavy chain gene and sarcoplasmic reticulum Ca2 + ATPase genes, which play pivotal role in development of cardiac dysfunction in HFrEF.[30]

Protein kinase B/C signalling

  • It has been shown that acute inhibition of a kinase independent of direct calcium load or myosin activation, PKCα/β, benefits contractile function of the heart and improves systolic function[31]

Mitogen-activated protein kinase (MAPK) cascade

  • MAPK pathway has been shown to induce cardiac hypertrophy and cardiac remodeling seen in heart failure.[32][33]
  • This pathway via various members of the MAPK family such as extracellular signal-regulated kinases, p38 kinase and c-jun N-terminal protein kinases (JNKs).[34][35]
  • Cell stretch or ischemia triggers these pathways which ultimately lead to formation of leucine zipper transcription factors.

Dysregulation of cellular protein metabolic pathways

Role of extracellular signal-regulated kinases (ERK1 and ERK2) pathways

  • ERK 1 and 2 are consitutively activated through serial phosphorylation as a part of the RAS-RAF-MEK-ERK pathway.[36] [37]
  • Receptor tyrosine kinases in response to growth factors lead to stimulation of RAS through recruitment of SOS exchange factor. RAS facilitates the activation of MEK-ERK cascade through constitutive phosphorylation. Angiotensin II, endothelin-1 or α-adrenergic agonists lead to stimulation of this G protein coupled receptor which in turn activates phospholipase C to catalyze the hydrolysis of phospholipids on the cytoplasmic side of the membrane to produce diacylglycerol (DAG) and inositol-3,4,5-triphosphate (InsP3). DAG then stimulates the lipid-dependent serine/threonine kinase protein kinase C (PKC) and Gβγ-protein to stimulate the ERK pathway.[38][39][40]
  • Once activated, ERK translocates to the nucleus and leads to phosphorylation of various transcription factors, ultimately leading to the transcription of hundreds of genes.
  • These become activated in response to G-protein coupled receptors in response to pathological stress on the failing heart and function in cardiac hypertrophy as a result of stress on the myocardium or cardiac stretch sensors, also known as membrane integrins.[41]
  • Beta-arrestin, a membrane bound integrin has been known to perform cross talk between G-protein coupled receptors and the RAS-RAF-MEK-ERK module.Other scaffold proteins involved include KSR, Shoc2, Erbin, IQGAP, Melusin, FHL1, and ANKRD1.[42][43]
  • Downregulation of ERK is known to result in the transition from compensated hypertrophy to maladaptive hypertrophic heart failure during pressure overload, and ERK is required to prevent eccentric growth secondary to pressure overload.[44]

Role of nitric oxide biosynthetic pathway

  • Dysregulation of nitric oxide (NO) production in the failing heart ultimately produces vascular stiffness, worsening diastolic dysfunction, and systemic and pulmonary vasoconstriction, consequently increasing left and right ventricular afterload.[45]
  • Production of NO takes place via two pathways, namely, the endothelial nitric oxide synthase (eNOS) pathway and the nitrate-nitrite-NO pathway.[46]
  • The nitrate-nitrite-NO pathway id the dominant route of NO production under conditions of hypoxia and acidosis. The NO produced as a result of these pathways ultimately diffuses into smooth muscle and myocardial cells where it stimulates soluble guanylate cyclase to produce cyclic guanosine monophosphate (cGMP). In smooth muscle cells, NO leads to smooth muscle relaxation and has anti-proliferative effects.[47]
  • In heart failure patients, inactivation of NO by superoxide anion and downregulation of eNOS, leads to reduction in levels of NO. This hampers the distensibility of the failing heart and adversely affects the myocardium.[48]

Smooth muscle cell proliferation

JNK mediated hypertrophy

  • The phosphorylation of c-jun, Sap-1 and ATF-2 by JNK has been shown to increase transcriptional activity and gene expression.[49][50][51][52]
  • SAPK/JNK is activated in ischemia/reperfusion. SAPKs are activated by ET-1 and phenylephrine, and are markedly activated by cytotoxic cellular stresses including osmotic or oxidative stress and function in decompensated hypertrophy[53]

Major biomarkers of HFrEF

NT-proBNP, GDF-15, and IL1RL1


  • Myocardial injury in heart failure activates both extrnisic and intrinsic pathways of apoptosis.
  • Activation of FAS-receptor by FAS-ligand results in activation of caspase 8 and downstream induction of caspases 3, 6 and 7 which lead to programmed cell death. This pathway represents activation of extrinsic cell death.
  • Increased mitochondrial permeability releases cytochrome C, apoptosis-inducing factor (AIF) and Smac/Diablo release, which activates the intrinsic apoptotic pathway.


  1. 1.0 1.1 Mercadier JJ, Lompré AM, Duc P, Boheler KR, Fraysse JB, Wisnewsky C, Allen PD, Komajda M, Schwartz K (January 1990). "Altered sarcoplasmic reticulum Ca2(+)-ATPase gene expression in the human ventricle during end-stage heart failure". J. Clin. Invest. 85 (1): 305–9. doi:10.1172/JCI114429. PMC 296420. PMID 2136864.
  2. Lala A, Desai AS (April 2014). "The role of coronary artery disease in heart failure". Heart Fail Clin. 10 (2): 353–65. doi:10.1016/j.hfc.2013.10.002. PMID 24656111.
  3. Velagaleti RS, Vasan RS (November 2007). "Heart failure in the twenty-first century: is it a coronary artery disease or hypertension problem?". Cardiol Clin. 25 (4): 487–95, v. doi:10.1016/j.ccl.2007.08.010. PMC 2350191. PMID 18063154.
  4. Messerli FH, Rimoldi SF, Bangalore S (August 2017). "The Transition From Hypertension to Heart Failure: Contemporary Update". JACC Heart Fail. 5 (8): 543–551. doi:10.1016/j.jchf.2017.04.012. PMID 28711447.
  5. Dubrey SW, Bell A, Mittal TK (October 2007). "Sarcoid heart disease". Postgrad Med J. 83 (984): 618–23. doi:10.1136/pgmj.2007.060608. PMC 2600123. PMID 17916869.
  6. Dhakal BP, Kim CH, Al-Kindi SG, Oliveira GH (April 2018). "Heart failure in systemic lupus erythematosus". Trends Cardiovasc. Med. 28 (3): 187–197. doi:10.1016/j.tcm.2017.08.015. PMID 28927572.
  7. Zeller CB, Appenzeller S (May 2008). "Cardiovascular disease in systemic lupus erythematosus: the role of traditional and lupus related risk factors". Curr Cardiol Rev. 4 (2): 116–22. doi:10.2174/157340308784245775. PMC 2779351. PMID 19936286.
  8. Djoussé L, Gaziano JM (April 2008). "Alcohol consumption and heart failure: a systematic review". Curr Atheroscler Rep. 10 (2): 117–20. doi:10.1007/s11883-008-0017-z. PMC 2365733. PMID 18417065.
  9. Lymperopoulos A, Rengo G, Koch WJ (August 2013). "Adrenergic nervous system in heart failure: pathophysiology and therapy". Circ. Res. 113 (6): 739–53. doi:10.1161/CIRCRESAHA.113.300308. PMC 3843360. PMID 23989716.
  10. Esler M, Kaye D, Lambert G, Esler D, Jennings G (December 1997). "Adrenergic nervous system in heart failure". Am. J. Cardiol. 80 (11A): 7L–14L. doi:10.1016/s0002-9149(97)00844-8. PMID 9412538.
  11. Unger T, Li J (September 2004). "The role of the renin-angiotensin-aldosterone system in heart failure". J Renin Angiotensin Aldosterone Syst. 5 Suppl 1: S7–10. doi:10.3317/jraas.2004.024. PMID 15526242.
  12. Johnston CI, Fabris B, Yoshida K (September 1993). "The cardiac renin-angiotensin system in heart failure". Am. Heart J. 126 (3 Pt 2): 756–60. doi:10.1016/0002-8703(93)90925-y. PMID 8362749.
  13. Ruffolo RR, Kopia GA (February 1986). "Importance of receptor regulation in the pathophysiology and therapy of congestive heart failure". Am. J. Med. 80 (2B): 67–72. doi:10.1016/0002-9343(86)90148-8. PMID 2868661.
  14. Bernstein D, Fajardo G, Zhao M (January 2011). "THE ROLE OF β-ADRENERGIC RECEPTORS IN HEART FAILURE: DIFFERENTIAL REGULATION OF CARDIOTOXICITY AND CARDIOPROTECTION". Prog. Pediatr. Cardiol. 31 (1): 35–38. doi:10.1016/j.ppedcard.2010.11.007. PMC 3135901. PMID 21765627.
  15. Ljungman S, Laragh JH, Cody RJ (1990). "Role of the kidney in congestive heart failure. Relationship of cardiac index to kidney function". Drugs. 39 Suppl 4: 10–21, discussion 22–4. doi:10.2165/00003495-199000394-00004. PMID 2354670.
  17. Damman K, Navis G, Smilde TD, Voors AA, van der Bij W, van Veldhuisen DJ, Hillege HL (September 2007). "Decreased cardiac output, venous congestion and the association with renal impairment in patients with cardiac dysfunction". Eur. J. Heart Fail. 9 (9): 872–8. doi:10.1016/j.ejheart.2007.05.010. PMID 17586090.
  18. Brunner-La Rocca HP, Sanders-van Wijk S (February 2019). "Natriuretic Peptides in Chronic Heart Failure". Card Fail Rev. 5 (1): 44–49. doi:10.15420/cfr.2018.26.1. PMC 6396059. PMID 30847245.
  19. Vuolteenaho O, Ala-Kopsala M, Ruskoaho H (2005). "BNP as a biomarker in heart disease". Adv Clin Chem. 40: 1–36. PMID 16355919.
  20. Brandt RR, Wright RS, Redfield MM, Burnett JC (October 1993). "Atrial natriuretic peptide in heart failure". J. Am. Coll. Cardiol. 22 (4 Suppl A): 86A–92A. doi:10.1016/0735-1097(93)90468-g. PMID 8376700.
  21. Cannon PJ (August 1986). "Prostaglandins in congestive heart failure and the effects of nonsteroidal anti-inflammatory drugs". Am. J. Med. 81 (2B): 123–32. doi:10.1016/0002-9343(86)90913-7. PMID 3092662.
  22. Cheng CP, Onishi K, Ohte N, Suzuki M, Little WC (June 1998). "Functional effects of endogenous bradykinin in congestive heart failure". J. Am. Coll. Cardiol. 31 (7): 1679–86. PMID 9626851.
  23. Lipskaia L, Hulot JS, Lompré AM (January 2009). "Role of sarco/endoplasmic reticulum calcium content and calcium ATPase activity in the control of cell growth and proliferation". Pflugers Arch. 457 (3): 673–85. doi:10.1007/s00424-007-0428-7. PMID 18188588.
  24. Marks AR (January 2013). "Calcium cycling proteins and heart failure: mechanisms and therapeutics". J. Clin. Invest. 123 (1): 46–52. doi:10.1172/JCI62834. PMC 3533269. PMID 23281409.
  25. Crossman DJ, Young AA, Ruygrok PN, Nason GP, Baddelely D, Soeller C, Cannell MB (July 2015). "T-tubule disease: Relationship between t-tubule organization and regional contractile performance in human dilated cardiomyopathy". J. Mol. Cell. Cardiol. 84: 170–8. doi:10.1016/j.yjmcc.2015.04.022. PMC 4467993. PMID 25953258.
  26. 26.0 26.1 Casals G, Ros J, Sionis A, Davidson MM, Morales-Ruiz M, Jiménez W (August 2009). "Hypoxia induces B-type natriuretic peptide release in cell lines derived from human cardiomyocytes". Am. J. Physiol. Heart Circ. Physiol. 297 (2): H550–5. doi:10.1152/ajpheart.00250.2009. PMID 19542490.
  27. Semenza GL (2014). "Hypoxia-inducible factor 1 and cardiovascular disease". Annu. Rev. Physiol. 76: 39–56. doi:10.1146/annurev-physiol-021113-170322. PMC 4696033. PMID 23988176.
  28. Movassagh M, Choy MK, Knowles DA, Cordeddu L, Haider S, Down T, Siggens L, Vujic A, Simeoni I, Penkett C, Goddard M, Lio P, Bennett MR, Foo RS (November 2011). "Distinct epigenomic features in end-stage failing human hearts". Circulation. 124 (22): 2411–22. doi:10.1161/CIRCULATIONAHA.111.040071. PMC 3634158. PMID 22025602.
  29. Maunakea AK, Nagarajan RP, Bilenky M, Ballinger TJ, D'Souza C, Fouse SD, Johnson BE, Hong C, Nielsen C, Zhao Y, Turecki G, Delaney A, Varhol R, Thiessen N, Shchors K, Heine VM, Rowitch DH, Xing X, Fiore C, Schillebeeckx M, Jones SJ, Haussler D, Marra MA, Hirst M, Wang T, Costello JF (July 2010). "Conserved role of intragenic DNA methylation in regulating alternative promoters". Nature. 466 (7303): 253–7. doi:10.1038/nature09165. PMC 3998662. PMID 20613842.
  30. Nakao K, Minobe W, Roden R, Bristow MR, Leinwand LA (November 1997). "Myosin heavy chain gene expression in human heart failure". J. Clin. Invest. 100 (9): 2362–70. doi:10.1172/JCI119776. PMC 508434. PMID 9410916.
  31. Pimental DR, Sam F (December 2017). "Is Protein Kinase C Inhibition the Tip of the Iceberg in New Therapeutics for Acutely Decompensated Heart Failure?". JACC Basic Transl Sci. 2 (6): 684–687. doi:10.1016/j.jacbts.2017.11.005. PMC 6066669. PMID 30069551.
  32. Malarkey K, Belham CM, Paul A, Graham A, McLees A, Scott PH, Plevin R (July 1995). "The regulation of tyrosine kinase signalling pathways by growth factor and G-protein-coupled receptors". Biochem. J. 309 ( Pt 2): 361–75. doi:10.1042/bj3090361. PMC 1135740. PMID 7625997.
  33. Hein L, Barsh GS, Pratt RE, Dzau VJ, Kobilka BK (October 1995). "Behavioural and cardiovascular effects of disrupting the angiotensin II type-2 receptor in mice". Nature. 377 (6551): 744–7. doi:10.1038/377744a0. PMID 7477266.
  34. Hibi M, Lin A, Smeal T, Minden A, Karin M (November 1993). "Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain". Genes Dev. 7 (11): 2135–48. doi:10.1101/gad.7.11.2135. PMID 8224842.
  35. "Norepinephrine Induces the raf-1 Kinase/Mitogen-Activated Protein Kinase Cascade Through Both α1- and β-Adrenoceptors | Circulation".
  36. Hefti MA, Harder BA, Eppenberger HM, Schaub MC (November 1997). "Signaling pathways in cardiac myocyte hypertrophy". J. Mol. Cell. Cardiol. 29 (11): 2873–92. doi:10.1006/jmcc.1997.0523. PMID 9405163.
  37. Steinberg SF, Goldberg M, Rybin VO (January 1995). "Protein kinase C isoform diversity in the heart". J. Mol. Cell. Cardiol. 27 (1): 141–53. doi:10.1016/s0022-2828(08)80014-4. PMID 7760339.
  38. Farnsworth CL, Freshney NW, Rosen LB, Ghosh A, Greenberg ME, Feig LA (August 1995). "Calcium activation of Ras mediated by neuronal exchange factor Ras-GRF". Nature. 376 (6540): 524–7. doi:10.1038/376524a0. PMID 7637786.
  39. Gille H, Sharrocks AD, Shaw PE (July 1992). "Phosphorylation of transcription factor p62TCF by MAP kinase stimulates ternary complex formation at c-fos promoter". Nature. 358 (6385): 414–7. doi:10.1038/358414a0. PMID 1322499.
  40. Han J, Lee JD, Bibbs L, Ulevitch RJ (August 1994). "A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells". Science. 265 (5173): 808–11. doi:10.1126/science.7914033. PMID 7914033.
  41. "Prime Time for JNK-Mediated Akt Reactivation in Hypoxia-Reoxygenation | Circulation Research".
  42. Noor N, Patel CB, Rockman HA (October 2011). "Β-arrestin: a signaling molecule and potential therapeutic target for heart failure". J. Mol. Cell. Cardiol. 51 (4): 534–41. doi:10.1016/j.yjmcc.2010.11.005. PMC 3063861. PMID 21074538.
  43. Jang ER, Galperin E (2016). "The function of Shoc2: A scaffold and beyond". Commun Integr Biol. 9 (4): e1188241. doi:10.1080/19420889.2016.1188241. PMC 4988449. PMID 27574535.
  44. Rose BA, Force T, Wang Y (October 2010). "Mitogen-activated protein kinase signaling in the heart: angels versus demons in a heart-breaking tale". Physiol. Rev. 90 (4): 1507–46. doi:10.1152/physrev.00054.2009. PMC 3808831. PMID 20959622.
  45. Liu VW, Huang PL (January 2008). "Cardiovascular roles of nitric oxide: a review of insights from nitric oxide synthase gene disrupted mice". Cardiovasc. Res. 77 (1): 19–29. doi:10.1016/j.cardiores.2007.06.024. PMC 2731989. PMID 17658499.
  46. Michel T, Vanhoutte PM (May 2010). "Cellular signaling and NO production". Pflugers Arch. 459 (6): 807–16. doi:10.1007/s00424-009-0765-9. PMC 3774002. PMID 20082095.
  47. Lundberg JO, Weitzberg E, Gladwin MT (February 2008). "The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics". Nat Rev Drug Discov. 7 (2): 156–67. doi:10.1038/nrd2466. PMID 18167491.
  48. Agnoletti L, Curello S, Bachetti T, Malacarne F, Gaia G, Comini L, Volterrani M, Bonetti P, Parrinello G, Cadei M, Grigolato PG, Ferrari R (November 1999). "Serum from patients with severe heart failure downregulates eNOS and is proapoptotic: role of tumor necrosis factor-alpha". Circulation. 100 (19): 1983–91. doi:10.1161/01.cir.100.19.1983. PMID 10556225.
  49. Clerk A, Michael A, Sugden PH (July 1998). "Stimulation of the p38 mitogen-activated protein kinase pathway in neonatal rat ventricular myocytes by the G protein-coupled receptor agonists, endothelin-1 and phenylephrine: a role in cardiac myocyte hypertrophy?". J. Cell Biol. 142 (2): 523–35. doi:10.1083/jcb.142.2.523. PMC 2133061. PMID 9679149.
  50. "c-Jun N-Terminal Kinase Activation Mediates Downregulation of Connexin43 in Cardiomyocytes | Circulation Research".
  51. Knight RJ, Buxton DB (January 1996). "Stimulation of c-Jun kinase and mitogen-activated protein kinase by ischemia and reperfusion in the perfused rat heart". Biochem. Biophys. Res. Commun. 218 (1): 83–8. doi:10.1006/bbrc.1996.0016. PMID 8573181.
  52. Bogoyevitch MA, Gillespie-Brown J, Ketterman AJ, Fuller SJ, Ben-Levy R, Ashworth A, Marshall CJ, Sugden PH (August 1996). "Stimulation of the stress-activated mitogen-activated protein kinase subfamilies in perfused heart. p38/RK mitogen-activated protein kinases and c-Jun N-terminal kinases are activated by ischemia/reperfusion". Circ. Res. 79 (2): 162–73. doi:10.1161/01.res.79.2.162. PMID 8755992.
  53. Wang Y, Huang S, Sah VP, Ross J, Brown JH, Han J, Chien KR (January 1998). "Cardiac muscle cell hypertrophy and apoptosis induced by distinct members of the p38 mitogen-activated protein kinase family". J. Biol. Chem. 273 (4): 2161–8. doi:10.1074/jbc.273.4.2161. PMID 9442057.