Congestive heart failure with reduced EF: Difference between revisions

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__NOTOC__
__NOTOC__
{{Congestive heart failure}}
{{Congestive heart failure}}
{{CMG}}; {{AE}}
{{CMG}}; {{AE}} {{HK}}


==Overview==
==Overview==
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]], [[Epigenetics|epigenetic]] modifications, changes in [[Sarcomere|sarcomeric]] coupling [[proteins]], increased [[adrenergic]] drive, increased activity of [[Renin angiotensin aldosterone system|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)==
==Heart Failure With Reduced Ejection Fraction (HFrEF)==
The pathogenesis of HFrEF is related largely to cellular proliferation and metabolism <br />
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]], [[Epigenetics|epigenetic]] modifications, changes in [[Sarcomere|sarcomeric]] coupling [[proteins]], increased [[adrenergic]] drive, increased activity of [[Renin angiotensin aldosterone system|renin-angiotensin aldosterone axis]], [[nitric oxide]] insensitivity, [[adenosine triphosphate]] (ATP) depletion, [[reactive oxygen species]] production and an elevated [[cell death]] rate.


=== Activation of DNA binding transcription factors ===
=== Precipitating factors ===
 
* Heart failure results from an initial injury to the heart such as due to [[myocardial infarction]] or [[hypertension]] and may also result from dysfunction of other [[organ systems]] with failure of the heart following a more insidious course. The end result is a decrease in [[myocardial]] [[contractility]] and reduced [[cardiac output]].<ref name="pmid2136864">{{cite journal |vauthors=Mercadier JJ, Lompré AM, Duc P, Boheler KR, Fraysse JB, Wisnewsky C, Allen PD, Komajda M, Schwartz K |title=Altered sarcoplasmic reticulum Ca2(+)-ATPase gene expression in the human ventricle during end-stage heart failure |journal=J. Clin. Invest. |volume=85 |issue=1 |pages=305–9 |date=January 1990 |pmid=2136864 |pmc=296420 |doi=10.1172/JCI114429 |url=}}</ref>
*[[Coronary artery disease]] and [[hypertension]] are the major precipitating factors in HFrEF. Other conditions that may lead to development of HFrEF include [[cardiomyopathies]], [[myocarditis]], [[Valvular heart disease|valvular]] abnormalities and [[cardiac]] infections.<ref name="pmid24656111">{{cite journal |vauthors=Lala A, Desai AS |title=The role of coronary artery disease in heart failure |journal=Heart Fail Clin |volume=10 |issue=2 |pages=353–65 |date=April 2014 |pmid=24656111 |doi=10.1016/j.hfc.2013.10.002 |url=}}</ref><ref name="pmid18063154">{{cite journal |vauthors=Velagaleti RS, Vasan RS |title=Heart failure in the twenty-first century: is it a coronary artery disease or hypertension problem? |journal=Cardiol Clin |volume=25 |issue=4 |pages=487–95; v |date=November 2007 |pmid=18063154 |pmc=2350191 |doi=10.1016/j.ccl.2007.08.010 |url=}}</ref><ref name="pmid28711447">{{cite journal |vauthors=Messerli FH, Rimoldi SF, Bangalore S |title=The Transition From Hypertension to Heart Failure: Contemporary Update |journal=JACC Heart Fail |volume=5 |issue=8 |pages=543–551 |date=August 2017 |pmid=28711447 |doi=10.1016/j.jchf.2017.04.012 |url=}}</ref>
*Extra cardiac conditions leading to the development of HFrEF include [[Hyperthyroidism|thyroid dysfunction]], [[sarcoidosis]], [[systemic lupus erythematosus]] and conditions related to a high intake of [[alcohol]] and other illicit drugs.<ref name="pmid17916869">{{cite journal |vauthors=Dubrey SW, Bell A, Mittal TK |title=Sarcoid heart disease |journal=Postgrad Med J |volume=83 |issue=984 |pages=618–23 |date=October 2007 |pmid=17916869 |pmc=2600123 |doi=10.1136/pgmj.2007.060608 |url=}}</ref><ref name="pmid28927572">{{cite journal |vauthors=Dhakal BP, Kim CH, Al-Kindi SG, Oliveira GH |title=Heart failure in systemic lupus erythematosus |journal=Trends Cardiovasc. Med. |volume=28 |issue=3 |pages=187–197 |date=April 2018 |pmid=28927572 |doi=10.1016/j.tcm.2017.08.015 |url=}}</ref><ref name="pmid19936286">{{cite journal |vauthors=Zeller CB, Appenzeller S |title=Cardiovascular disease in systemic lupus erythematosus: the role of traditional and lupus related risk factors |journal=Curr Cardiol Rev |volume=4 |issue=2 |pages=116–22 |date=May 2008 |pmid=19936286 |pmc=2779351 |doi=10.2174/157340308784245775 |url=}}</ref><ref name="pmid18417065">{{cite journal |vauthors=Djoussé L, Gaziano JM |title=Alcohol consumption and heart failure: a systematic review |journal=Curr Atheroscler Rep |volume=10 |issue=2 |pages=117–20 |date=April 2008 |pmid=18417065 |pmc=2365733 |doi=10.1007/s11883-008-0017-z |url=}}</ref>
*These factors or conditions may ultimately result in reduced [[cardiac]] [[contractility]] or increase the afterload leading to increased work done by the heart in order to maintain [[cardiac output]]
 
=== Increased adrenergic drive ===
 
* Reduced end-organ [[perfusion]] secondary to a decreased [[cardiac output]] in heart failure activates neurhormonal processes that aim to compensate for the failing heart.
* In an effort to preserve the [[ejection fraction]], the [[sympathetic system]] is activated and the [[adrenal medulla]] secretes [[catecholamines]] which can now act via [[beta-1 receptors]] found in [[cardiac]] [[myocytes]] and improve [[contractility]].<ref name="pmid23989716">{{cite journal |vauthors=Lymperopoulos A, Rengo G, Koch WJ |title=Adrenergic nervous system in heart failure: pathophysiology and therapy |journal=Circ. Res. |volume=113 |issue=6 |pages=739–53 |date=August 2013 |pmid=23989716 |pmc=3843360 |doi=10.1161/CIRCRESAHA.113.300308 |url=}}</ref><ref name="pmid9412538">{{cite journal |vauthors=Esler M, Kaye D, Lambert G, Esler D, Jennings G |title=Adrenergic nervous system in heart failure |journal=Am. J. Cardiol. |volume=80 |issue=11A |pages=7L–14L |date=December 1997 |pmid=9412538 |doi=10.1016/s0002-9149(97)00844-8 |url=}}</ref>
* Similarly in the [[kidneys]], stimulation of [[beta-1 receptors]] activates the [[renin-angiotensin-aldosterone axis]], which as a compensatory mechanism retains more [[sodium]] and water in the body in an effort to increase the [[Preload (cardiology)|pre-load]] and increase [[cardiac output]].<ref name="pmid15526242">{{cite journal |vauthors=Unger T, Li J |title=The role of the renin-angiotensin-aldosterone system in heart failure |journal=J Renin Angiotensin Aldosterone Syst |volume=5 Suppl 1 |issue= |pages=S7–10 |date=September 2004 |pmid=15526242 |doi=10.3317/jraas.2004.024 |url=}}</ref><ref name="pmid8362749">{{cite journal |vauthors=Johnston CI, Fabris B, Yoshida K |title=The cardiac renin-angiotensin system in heart failure |journal=Am. Heart J. |volume=126 |issue=3 Pt 2 |pages=756–60 |date=September 1993 |pmid=8362749 |doi=10.1016/0002-8703(93)90925-y |url=}}</ref>
* A prolonged period of increased [[adrenergic]] drive ultimately leads to [[downregulation]] of [[cardiac]] [[Beta receptors|beta-receptors]] which ultimately results in a poor [[inotropic]] response.<ref name="pmid2868661">{{cite journal |vauthors=Ruffolo RR, Kopia GA |title=Importance of receptor regulation in the pathophysiology and therapy of congestive heart failure |journal=Am. J. Med. |volume=80 |issue=2B |pages=67–72 |date=February 1986 |pmid=2868661 |doi=10.1016/0002-9343(86)90148-8 |url=}}</ref><ref name="pmid21765627">{{cite journal |vauthors=Bernstein D, Fajardo G, Zhao M |title=THE ROLE OF β-ADRENERGIC RECEPTORS IN HEART FAILURE: DIFFERENTIAL REGULATION OF CARDIOTOXICITY AND CARDIOPROTECTION |journal=Prog. Pediatr. Cardiol. |volume=31 |issue=1 |pages=35–38 |date=January 2011 |pmid=21765627 |pmc=3135901 |doi=10.1016/j.ppedcard.2010.11.007 |url=}}</ref>
*The increased [[adrenergic]] drive also leads to [[tachycardia]] and increased predisposition to development of various [[Cardiac arrhythmia|arrhythmias]].
 
=== Renin-angiotensin aldosterone pathway ===
 
* In heart failure, reduced [[renal blood flow]] and [[efferent arteriole]] constriction due to decreased [[cardiac output]] are some of the early [[renal]] effects seen.<ref name="pmid2354670">{{cite journal |vauthors=Ljungman S, Laragh JH, Cody RJ |title=Role of the kidney in congestive heart failure. Relationship of cardiac index to kidney function |journal=Drugs |volume=39 Suppl 4 |issue= |pages=10–21; discussion 22–4 |date=1990 |pmid=2354670 |doi=10.2165/00003495-199000394-00004 |url=}}</ref>
* The reduced [[renal blood flow]] and resulting decreased [[glomerular filtration rate]] leads to reduced [[sodium]] filtered into the renal tubules for absorption. This is augmented by an elevated production of [[renin]] giving rise to increased [[angiotensin II]] in an effort to maintain [[renal blood flow]]. Though compensatory, the unchecked activation of the [[Renin-angiotensin-aldosterone system|renin-angiotensin-aldosterone]] adversely effects the body.<ref name="pmid16695330">{{cite journal |vauthors=Merrill AJ |title=EDEMA AND DECREASED RENAL BLOOD FLOW IN PATIENTS WITH CHRONIC CONGESTIVE HEART FAILURE: EVIDENCE OF "FORWARD FAILURE" AS THE PRIMARY CAUSE OF EDEMA |journal=J. Clin. Invest. |volume=25 |issue=3 |pages=389–400 |date=May 1946 |pmid=16695330 |pmc=435576 |doi=10.1172/JCI101720 |url=}}</ref><ref name="pmid17586090">{{cite journal |vauthors=Damman K, Navis G, Smilde TD, Voors AA, van der Bij W, van Veldhuisen DJ, Hillege HL |title=Decreased cardiac output, venous congestion and the association with renal impairment in patients with cardiac dysfunction |journal=Eur. J. Heart Fail. |volume=9 |issue=9 |pages=872–8 |date=September 2007 |pmid=17586090 |doi=10.1016/j.ejheart.2007.05.010 |url=}}</ref>
* The ultimate result is a state of [[fluid overload]] that leads to many of the effects seen in heart failure patients.
 
=== Impact on the Frank Starling curve ===
 
* Heart failure is characterized by decreased [[inotropy]] which leads to shifting down of the [[Frank-Starling mechanism|Frank-Starling curve]], the result is a decreased [[cardiac output]] so that an increased [[Preload (cardiology)|preload]] is required to compensate. This leads to an accumulation of [[blood]] in the [[ventricle]] at the end of [[diastole]] (that is, an increase in [[end diastolic volume]]), which increases the stretch of the [[ventricles]] (and, at the [[cellular]] level, increases [[myocardial]] fibre stretch), thereby increasing the strength of subsequent [[ventricular]] contraction and increasing [[stroke volume]], which allows the emptying of the enlarged [[left ventricle]].
*However, this mechanism falls short in HFrEF when a reduction in [[cardiovascular]] reserve (that is, the difference between the rate at which the heart can pump [[blood]] and the maximum capacity to pump blood) results in [[ventricular]] impairment and reduced [[ventricular]] contraction, leading to a reduction in [[stroke volume]], [[cardiac output]] and an increase in [[end diastolic volume]]
*Indeed, in decompensated heart failure the elevated [[end-diastolic volume]] or left and right [[atrial]] pressure produces most of congestive [[symptoms]] associated with heart failure.
 
=== Counter-balancing factors to increased adrenergic drive ===
 
* The activation of the [[Sympathetic nervous system|sympathetic system]] in the body upregulates the production of factors that tend to rid the body of excess fluid through [[Urine|natriuresis]], [[diuresis]] and [[vasodilation]].
* These factors include:<ref name="pmid30847245">{{cite journal |vauthors=Brunner-La Rocca HP, Sanders-van Wijk S |title=Natriuretic Peptides in Chronic Heart Failure |journal=Card Fail Rev |volume=5 |issue=1 |pages=44–49 |date=February 2019 |pmid=30847245 |pmc=6396059 |doi=10.15420/cfr.2018.26.1 |url=}}</ref><ref name="pmid16355919">{{cite journal |vauthors=Vuolteenaho O, Ala-Kopsala M, Ruskoaho H |title=BNP as a biomarker in heart disease |journal=Adv Clin Chem |volume=40 |issue= |pages=1–36 |date=2005 |pmid=16355919 |doi= |url=}}</ref><ref name="pmid8376700">{{cite journal |vauthors=Brandt RR, Wright RS, Redfield MM, Burnett JC |title=Atrial natriuretic peptide in heart failure |journal=J. Am. Coll. Cardiol. |volume=22 |issue=4 Suppl A |pages=86A–92A |date=October 1993 |pmid=8376700 |doi=10.1016/0735-1097(93)90468-g |url=}}</ref><ref name="pmid3092662">{{cite journal |vauthors=Cannon PJ |title=Prostaglandins in congestive heart failure and the effects of nonsteroidal anti-inflammatory drugs |journal=Am. J. Med. |volume=81 |issue=2B |pages=123–32 |date=August 1986 |pmid=3092662 |doi=10.1016/0002-9343(86)90913-7 |url=}}</ref><ref name="pmid9626851">{{cite journal |vauthors=Cheng CP, Onishi K, Ohte N, Suzuki M, Little WC |title=Functional effects of endogenous bradykinin in congestive heart failure |journal=J. Am. Coll. Cardiol. |volume=31 |issue=7 |pages=1679–86 |date=June 1998 |pmid=9626851 |doi= |url=}}</ref>
**[[Bradykinin]]
**[[Brain natriuretic peptide|Brain-natriuretic peptide]] ([[Brain natriuretic peptide|BNP]])
**[[Atrial-natriuretic peptide]] ([[Atrial natriuretic peptide|ANP]])
**[[Prostaglandins]]
 
*[[Natriuretic peptides]] lead to increased [[Human urine|natriuresis]] (increased [[Urinary system|urinary]] [[sodium]] excretion) and [[diuresis]]. These peptides alongwith [[bradykinin]] and [[prostaglandins]] also lead to [[vasodilation]] in an effort to decrease intravascular resistance through acting on beta-2 receptors for the failing heart.
* Over time, reduced availability of active peptides and decreased end-organ response fails to compensate for heart failure.
 
=== Dysregulated excitation-contraction coupling ===
 
* Dysregulated [[excitation-contraction coupling]] in [[cardiac]] [[myocytes]] has been seen in the failing heart. It has been shown that there is reduced transient Ca currents from the [[sarcoplasmic reticulum]] in [[Cardiomyocyte|cardiomyocytes]] during heart failure.<ref name="pmid2136864">{{cite journal |vauthors=Mercadier JJ, Lompré AM, Duc P, Boheler KR, Fraysse JB, Wisnewsky C, Allen PD, Komajda M, Schwartz K |title=Altered sarcoplasmic reticulum Ca2(+)-ATPase gene expression in the human ventricle during end-stage heart failure |journal=J. Clin. Invest. |volume=85 |issue=1 |pages=305–9 |date=January 1990 |pmid=2136864 |pmc=296420 |doi=10.1172/JCI114429 |url=}}</ref>
* Alterations in Ca2+ handling have been ascribed to impaired function of the [[Ryanodine receptor|ryanodine receptors]], [[sarcoplasmic reticulum]] Ca2+ ATPase 2a , Na+–Ca2+ exchanger (NCX), and transient receptor potential cation (TRPC) channels.<ref name="pmid18188588">{{cite journal |vauthors=Lipskaia L, Hulot JS, Lompré AM |title=Role of sarco/endoplasmic reticulum calcium content and calcium ATPase activity in the control of cell growth and proliferation |journal=Pflugers Arch. |volume=457 |issue=3 |pages=673–85 |date=January 2009 |pmid=18188588 |doi=10.1007/s00424-007-0428-7 |url=}}</ref><ref name="pmid23281409">{{cite journal |vauthors=Marks AR |title=Calcium cycling proteins and heart failure: mechanisms and therapeutics |journal=J. Clin. Invest. |volume=123 |issue=1 |pages=46–52 |date=January 2013 |pmid=23281409 |pmc=3533269 |doi=10.1172/JCI62834 |url=}}</ref><ref name="pmid25953258">{{cite journal |vauthors=Crossman DJ, Young AA, Ruygrok PN, Nason GP, Baddelely D, Soeller C, Cannell MB |title=T-tubule disease: Relationship between t-tubule organization and regional contractile performance in human dilated cardiomyopathy |journal=J. Mol. Cell. Cardiol. |volume=84 |issue= |pages=170–8 |date=July 2015 |pmid=25953258 |pmc=4467993 |doi=10.1016/j.yjmcc.2015.04.022 |url=}}</ref>
 
=== 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.
* 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.<ref name="pmid26223692">{{cite journal |vauthors=Li G, Lu WH, Wu XW, Cheng J, Ai R, Zhou ZH, Tang ZZ |title=Admission hypoxia-inducible factor 1α levels and in-hospital mortality in patients with acute decompensated heart failure |journal=BMC Cardiovasc Disord |volume=15 |issue= |pages=79 |date=July 2015 |pmid=26223692 |pmc=4518524 |doi=10.1186/s12872-015-0073-6 |url=}}</ref>
*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.<ref name="pmid19542490">{{cite journal |vauthors=Casals G, Ros J, Sionis A, Davidson MM, Morales-Ruiz M, Jiménez W |title=Hypoxia induces B-type natriuretic peptide release in cell lines derived from human cardiomyocytes |journal=Am. J. Physiol. Heart Circ. Physiol. |volume=297 |issue=2 |pages=H550–5 |date=August 2009 |pmid=19542490 |doi=10.1152/ajpheart.00250.2009 |url=}}</ref><ref name="pmid19542490">{{cite journal |vauthors=Casals G, Ros J, Sionis A, Davidson MM, Morales-Ruiz M, Jiménez W |title=Hypoxia induces B-type natriuretic peptide release in cell lines derived from human cardiomyocytes |journal=Am. J. Physiol. Heart Circ. Physiol. |volume=297 |issue=2 |pages=H550–5 |date=August 2009 |pmid=19542490 |doi=10.1152/ajpheart.00250.2009 |url=}}</ref><ref name="pmid23988176">{{cite journal |vauthors=Semenza GL |title=Hypoxia-inducible factor 1 and cardiovascular disease |journal=Annu. Rev. Physiol. |volume=76 |issue= |pages=39–56 |date=2014 |pmid=23988176 |pmc=4696033 |doi=10.1146/annurev-physiol-021113-170322 |url=}}</ref>
*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.<ref name="pmid22025602">{{cite journal |vauthors=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 |title=Distinct epigenomic features in end-stage failing human hearts |journal=Circulation |volume=124 |issue=22 |pages=2411–22 |date=November 2011 |pmid=22025602 |pmc=3634158 |doi=10.1161/CIRCULATIONAHA.111.040071 |url=}}</ref><ref name="pmid20613842">{{cite journal |vauthors=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 |title=Conserved role of intragenic DNA methylation in regulating alternative promoters |journal=Nature |volume=466 |issue=7303 |pages=253–7 |date=July 2010 |pmid=20613842 |pmc=3998662 |doi=10.1038/nature09165 |url=}}</ref>
*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.<ref name="pmid9410916">{{cite journal |vauthors=Nakao K, Minobe W, Roden R, Bristow MR, Leinwand LA |title=Myosin heavy chain gene expression in human heart failure |journal=J. Clin. Invest. |volume=100 |issue=9 |pages=2362–70 |date=November 1997 |pmid=9410916 |pmc=508434 |doi=10.1172/JCI119776 |url=}}</ref>
 
==== 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<ref name="pmid30069551">{{cite journal |vauthors=Pimental DR, Sam F |title=Is Protein Kinase C Inhibition the Tip of the Iceberg in New Therapeutics for Acutely Decompensated Heart Failure? |journal=JACC Basic Transl Sci |volume=2 |issue=6 |pages=684–687 |date=December 2017 |pmid=30069551 |pmc=6066669 |doi=10.1016/j.jacbts.2017.11.005 |url=}}</ref>
 
==== Mitogen-activated protein kinase (MAPK) cascade ====
 
* MAPK pathway has been shown to induce cardiac hypertrophy and cardiac remodeling seen in heart failure.<ref name="pmid7625997">{{cite journal |vauthors=Malarkey K, Belham CM, Paul A, Graham A, McLees A, Scott PH, Plevin R |title=The regulation of tyrosine kinase signalling pathways by growth factor and G-protein-coupled receptors |journal=Biochem. J. |volume=309 ( Pt 2) |issue= |pages=361–75 |date=July 1995 |pmid=7625997 |pmc=1135740 |doi=10.1042/bj3090361 |url=}}</ref><ref name="pmid7477266">{{cite journal |vauthors=Hein L, Barsh GS, Pratt RE, Dzau VJ, Kobilka BK |title=Behavioural and cardiovascular effects of disrupting the angiotensin II type-2 receptor in mice |journal=Nature |volume=377 |issue=6551 |pages=744–7 |date=October 1995 |pmid=7477266 |doi=10.1038/377744a0 |url=}}</ref>
* 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).<ref name="pmid8224842">{{cite journal |vauthors=Hibi M, Lin A, Smeal T, Minden A, Karin M |title=Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain |journal=Genes Dev. |volume=7 |issue=11 |pages=2135–48 |date=November 1993 |pmid=8224842 |doi=10.1101/gad.7.11.2135 |url=}}</ref><ref name="urlNorepinephrine Induces the raf-1 Kinase/Mitogen-Activated Protein Kinase Cascade Through Both α1- and β-Adrenoceptors | Circulation">{{cite web |url=https://ahajournals.org/doi/full/10.1161/01.cir.95.5.1260 |title=Norepinephrine Induces the raf-1 Kinase/Mitogen-Activated Protein Kinase Cascade Through Both α1- and β-Adrenoceptors &#124; Circulation |format= |work= |accessdate=}}</ref>
* Cell stretch or ischemia triggers these pathways which ultimately lead to formation of leucine zipper transcription factors.
 
==== Dysregulation of cellular protein metabolic pathways ====
 
*


=== Protein kinase B signalling ===
==== Role of extracellular signal-regulated kinases (ERK1 and ERK2) pathways ====


=== MAPK cascade ===
* ERK 1 and 2 are consitutively activated through serial phosphorylation as a part of the RAS-RAF-MEK-ERK pathway.<ref name="pmid9405163">{{cite journal |vauthors=Hefti MA, Harder BA, Eppenberger HM, Schaub MC |title=Signaling pathways in cardiac myocyte hypertrophy |journal=J. Mol. Cell. Cardiol. |volume=29 |issue=11 |pages=2873–92 |date=November 1997 |pmid=9405163 |doi=10.1006/jmcc.1997.0523 |url=}}</ref> <ref name="pmid7760339">{{cite journal |vauthors=Steinberg SF, Goldberg M, Rybin VO |title=Protein kinase C isoform diversity in the heart |journal=J. Mol. Cell. Cardiol. |volume=27 |issue=1 |pages=141–53 |date=January 1995 |pmid=7760339 |doi=10.1016/s0022-2828(08)80014-4 |url=}}</ref>
<br />
*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.<ref name="pmid7637786">{{cite journal |vauthors=Farnsworth CL, Freshney NW, Rosen LB, Ghosh A, Greenberg ME, Feig LA |title=Calcium activation of Ras mediated by neuronal exchange factor Ras-GRF |journal=Nature |volume=376 |issue=6540 |pages=524–7 |date=August 1995 |pmid=7637786 |doi=10.1038/376524a0 |url=}}</ref><ref name="pmid1322499">{{cite journal |vauthors=Gille H, Sharrocks AD, Shaw PE |title=Phosphorylation of transcription factor p62TCF by MAP kinase stimulates ternary complex formation at c-fos promoter |journal=Nature |volume=358 |issue=6385 |pages=414–7 |date=July 1992 |pmid=1322499 |doi=10.1038/358414a0 |url=}}</ref><ref name="pmid7914033">{{cite journal |vauthors=Han J, Lee JD, Bibbs L, Ulevitch RJ |title=A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells |journal=Science |volume=265 |issue=5173 |pages=808–11 |date=August 1994 |pmid=7914033 |doi=10.1126/science.7914033 |url=}}</ref>
*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.<ref name="urlPrime Time for JNK-Mediated Akt Reactivation in Hypoxia-Reoxygenation | Circulation Research">{{cite web |url=https://www.ahajournals.org/doi/full/10.1161/01.res.0000200397.22663.b6 |title=Prime Time for JNK-Mediated Akt Reactivation in Hypoxia-Reoxygenation &#124; Circulation Research |format= |work= |accessdate=}}</ref>
* 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.<ref name="pmid21074538">{{cite journal |vauthors=Noor N, Patel CB, Rockman HA |title=Β-arrestin: a signaling molecule and potential therapeutic target for heart failure |journal=J. Mol. Cell. Cardiol. |volume=51 |issue=4 |pages=534–41 |date=October 2011 |pmid=21074538 |pmc=3063861 |doi=10.1016/j.yjmcc.2010.11.005 |url=}}</ref><ref name="pmid27574535">{{cite journal |vauthors=Jang ER, Galperin E |title=The function of Shoc2: A scaffold and beyond |journal=Commun Integr Biol |volume=9 |issue=4 |pages=e1188241 |date=2016 |pmid=27574535 |pmc=4988449 |doi=10.1080/19420889.2016.1188241 |url=}}</ref>
* 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.<ref name="pmid20959622">{{cite journal |vauthors=Rose BA, Force T, Wang Y |title=Mitogen-activated protein kinase signaling in the heart: angels versus demons in a heart-breaking tale |journal=Physiol. Rev. |volume=90 |issue=4 |pages=1507–46 |date=October 2010 |pmid=20959622 |pmc=3808831 |doi=10.1152/physrev.00054.2009 |url=}}</ref>


=== Dysregulation of cellular protein metabolic pathways ===
==== Role of nitric oxide biosynthetic pathway ====


=== Role of ERK1 and ERK2 pathways ===
* 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.<ref name="pmid17658499">{{cite journal |vauthors=Liu VW, Huang PL |title=Cardiovascular roles of nitric oxide: a review of insights from nitric oxide synthase gene disrupted mice |journal=Cardiovasc. Res. |volume=77 |issue=1 |pages=19–29 |date=January 2008 |pmid=17658499 |pmc=2731989 |doi=10.1016/j.cardiores.2007.06.024 |url=}}</ref>
*Production of NO takes place via two pathways, namely, the endothelial nitric oxide synthase (eNOS) pathway and the nitrate-nitrite-NO pathway.<ref name="pmid20082095">{{cite journal |vauthors=Michel T, Vanhoutte PM |title=Cellular signaling and NO production |journal=Pflugers Arch. |volume=459 |issue=6 |pages=807–16 |date=May 2010 |pmid=20082095 |pmc=3774002 |doi=10.1007/s00424-009-0765-9 |url=}}</ref>
*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.<ref name="pmid18167491">{{cite journal |vauthors=Lundberg JO, Weitzberg E, Gladwin MT |title=The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics |journal=Nat Rev Drug Discov |volume=7 |issue=2 |pages=156–67 |date=February 2008 |pmid=18167491 |doi=10.1038/nrd2466 |url=}}</ref>
*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.<ref name="pmid10556225">{{cite journal |vauthors=Agnoletti L, Curello S, Bachetti T, Malacarne F, Gaia G, Comini L, Volterrani M, Bonetti P, Parrinello G, Cadei M, Grigolato PG, Ferrari R |title=Serum from patients with severe heart failure downregulates eNOS and is proapoptotic: role of tumor necrosis factor-alpha |journal=Circulation |volume=100 |issue=19 |pages=1983–91 |date=November 1999 |pmid=10556225 |doi=10.1161/01.cir.100.19.1983 |url=}}</ref>


=== Role of nitric oxide biosynthetic pathway ===
==== Smooth muscle cell proliferation ====


=== Smooth muscle cell proliferation ===
*


=== ATF2 mediated hypertrophy ===
==== 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.<ref name="pmid9679149">{{cite journal |vauthors=Clerk A, Michael A, Sugden PH |title=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? |journal=J. Cell Biol. |volume=142 |issue=2 |pages=523–35 |date=July 1998 |pmid=9679149 |pmc=2133061 |doi=10.1083/jcb.142.2.523 |url=}}</ref><ref name="urlc-Jun N-Terminal Kinase Activation Mediates Downregulation of Connexin43 in Cardiomyocytes | Circulation Research">{{cite web |url=https://www.ahajournals.org/doi/10.1161/01.RES.0000035854.11082.01 |title=c-Jun N-Terminal Kinase Activation Mediates Downregulation of Connexin43 in Cardiomyocytes &#124; Circulation Research |format= |work= |accessdate=}}</ref><ref name="pmid8573181">{{cite journal |vauthors=Knight RJ, Buxton DB |title=Stimulation of c-Jun kinase and mitogen-activated protein kinase by ischemia and reperfusion in the perfused rat heart |journal=Biochem. Biophys. Res. Commun. |volume=218 |issue=1 |pages=83–8 |date=January 1996 |pmid=8573181 |doi=10.1006/bbrc.1996.0016 |url=}}</ref><ref name="pmid8755992">{{cite journal |vauthors=Bogoyevitch MA, Gillespie-Brown J, Ketterman AJ, Fuller SJ, Ben-Levy R, Ashworth A, Marshall CJ, Sugden PH |title=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 |journal=Circ. Res. |volume=79 |issue=2 |pages=162–73 |date=August 1996 |pmid=8755992 |doi=10.1161/01.res.79.2.162 |url=}}</ref>
* 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<ref name="pmid9442057">{{cite journal |vauthors=Wang Y, Huang S, Sah VP, Ross J, Brown JH, Han J, Chien KR |title=Cardiac muscle cell hypertrophy and apoptosis induced by distinct members of the p38 mitogen-activated protein kinase family |journal=J. Biol. Chem. |volume=273 |issue=4 |pages=2161–8 |date=January 1998 |pmid=9442057 |doi=10.1074/jbc.273.4.2161 |url=}}</ref>


=== Major biomarkers of HFrEF ===
=== Major biomarkers of HFrEF ===
NT-proBNP, GDF-15, and IL1RL1
NT-proBNP, GDF-15, and IL1RL1
==== Apoptosis ====
* 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.
*
==References==
{{reflist|2}}

Latest revision as of 16:12, 30 January 2020

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

Overview

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

Apoptosis

  • 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.

References

  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.
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  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.
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  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.
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  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.
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  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.
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