Congestive heart failure with reduced EF

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

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.
• 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.
• 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

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.

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. 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.
• 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.

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.
• 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

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.