Congestive heart failure with reduced EF: Difference between revisions
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* 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. | * 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. | ||
* 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. | * 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 | * 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 === | === Role of nitric oxide biosynthetic pathway === | ||
* Dysregulation of nitric oxide production in the failing heart ultimately produces vascular stiffness, worsening diastolic dysfunction, and systemic and pulmonary vasoconstriction, consequently increasing left and right ventricular afterload. | * 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 === | === Smooth muscle cell proliferation === | ||
Revision as of 21:59, 12 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.
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.
- 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).
- 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.
- 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 .
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.
- 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. 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.
- 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
ATF2 mediated hypertrophy
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
- ↑ 1.0 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.