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.

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 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.^[1]
• 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 abnormalities and cardiac infections.^[2][3][4]
• Extra cardiac conditions leading to the development of HFrEF include thyroid dysfunction, sarcoidosis, systemic lupus erythematosus and conditions related to a high intake of alcohol and other illicit drugs.^[5][6][7][8]
• 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

• 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.^[9][10]
• 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 pre-load and increase cardiac output.^[11][12]
• A prolonged period of increased adrenergic drive ultimately leads to downregulation of cardiac beta-receptors which ultimately results in a poor inotropic response.^[13][14]
• The increased adrenergic drive also leads to tachycardia and increased predisposition to development of various arrhythmias.

• In heart failure, reduced renal blood flow and efferent arteriole constriction due to decreased cardiac output are some of the early renal effects seen.^[15]
• 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 adversely effects the body.^[16][17]
• The ultimate result is a state of fluid overload that leads to many of the effects seen in heart failure patients.

• 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. 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.

• The activation of the sympathetic system in the body upregulates the production of factors that tend to rid the body of excess fluid through natriuresis, diuresis and vasodilation.
• These factors include:^{[18][19][20][21][22]}
  • Bradykinin
  • Brain-natriuretic peptide (BNP)
  • Atrial-natriuretic peptide (ANP)
  • Prostaglandins

• Natriuretic peptides lead to increased natriuresis (increased 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 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.^[1]
• Alterations in Ca2+ handling have been ascribed to impaired function of the ryanodine receptors, sarcoplasmic reticulum Ca2+ ATPase 2a , Na+–Ca2+ exchanger (NCX), and transient receptor potential cation (TRPC) channels.^[23][24][25]

• 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]

• 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]

• 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]_Circulation-35|[35]}
• Cell stretch or ischemia triggers these pathways which ultimately lead to formation of leucine zipper transcription factors.

• 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.^{_Circulation_Research-41|[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]

• 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]

• The phosphorylation of c-jun, Sap-1 and ATF-2 by JNK has been shown to increase transcriptional activity and gene expression.^{[49]_Circulation_Research-50|[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]

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.