Congestive heart failure with reduced EF: Difference between revisions
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==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. 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, adensoine triphosphate (ATP) depletion, reactive oxygen species production and an elevated cell death rate. <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, epigenetic modifications, changes in sarcomeric coupling proteins, increased adrenergic drive, increased activity of renin-angiotensin aldosterone axis, nitric oxide insensitivity, adensoine triphosphate (ATP) depletion, reactive oxygen species production and an elevated cell death rate. | ||
=== Precipitating factors === | |||
* Heart failure results from an initial injury to the heart such as myocardial infarction or may also result from dysfunction of other organ systems. The end result is a decrease in myocardial contractility and reduced cardiac output. <br /> | |||
=== Activation of DNA binding transcription factors === | === Activation of DNA binding transcription factors === | ||
Revision as of 16:44, 16 January 2020
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
Overview
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, adensoine triphosphate (ATP) depletion, reactive oxygen species production and an elevated cell death rate.
Precipitating factors
- Heart failure results from an initial injury to the heart such as myocardial infarction or may also result from dysfunction of other organ systems. The end result is a decrease in myocardial contractility and reduced cardiac output.
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.[1][1][2]
- 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.[3][4]
- 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.
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[5]
Mitogen-activated protein kinase (MAPK) cascade
- MAPK pathway has been shown to induce cardiac hypertrophy and cardiac remodeling seen in heart failure.[6][7]
- 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).[8][9]
- Cell stretch or ischemia triggers these pathways which ultimately lead to formation of leucine zipper transcription factors.
Dysregulation of cellular protein metabolic pathways
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 cardiomyocytes during heart failure.[10]
- Alterations in Ca2+ handling have been ascribed to impaired function of the ryanodine receptors, sarcoplasmis reticulum Ca2+ ATPase 2a , Na+–Ca2+ exchanger (NCX), and transient receptor potential cation (TRPC) channels.[11][12][13]
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.[14] [15]
- 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.[16][17][18]
- 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.[19]
- 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.
- 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.
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.
- Production of NO takes place via two pathways, namely, the endothelial nitric oxide synthase (eNOS) pathway and the nitrate-nitrite-NO pathway.
- 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.
- 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.
Smooth muscle cell proliferation
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.
- The reduced renal blood flow and resulting decreased glomerular filtration rate leads to reduced sodium present in 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-angitensin-aldosterone adversely effects the body.
- The ultimate result is a state of fluid overload that leads to many of the effects seen in heart failure patients.
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.[20][21][22][23]
- 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[24]
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.
Impact on the Frank Starling curve
- Heart failure is characterized by decreased inotropy which leads to shifting down of the Frank-Starling curve, the result is a decreased cardiac output so that an increased preload is required to compensate. Indeed, in decompensated heart failure the elevated end-distolic volume or right atrial pressure produces most of congestive symptoms associated with heart failure.
References
- ↑ 1.0 1.1 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ "Norepinephrine Induces the raf-1 Kinase/Mitogen-Activated Protein Kinase Cascade Through Both α1- and β-Adrenoceptors | Circulation".
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ "Prime Time for JNK-Mediated Akt Reactivation in Hypoxia-Reoxygenation | Circulation Research".
- ↑ 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.
- ↑ "c-Jun N-Terminal Kinase Activation Mediates Downregulation of Connexin43 in Cardiomyocytes | Circulation Research".
- ↑ 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.
- ↑ 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.
- ↑ 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.