Tackling heart failure in the twenty-first century

Abstract

Heart failure, or congestive heart failure, is a condition in which the heart cannot supply the body's tissues with enough blood. The result is a cascade of changes that lead to severe fatigue, breathlessness and, ultimately, death. In the past quarter century, much progress has been made in understanding the molecular and cellular processes that contribute to heart failure, leading to the development of effective therapies. Despite this, chronic heart failure remains a major cause of illness and death. And because the condition becomes more common with increasing age, the number of affected individuals is rising with the rapidly ageing global population. New treatments that target disease mechanisms at the cellular and whole-organ level are needed to halt and reverse the devastating consequences of this disease.

Network Reconstruction and Systems Analysis of Cardiac Myocyte Hypertrophy Signaling

“…1). The model contains 17 receptor inputs (tumor necrosis factor ␣ (TNF␣), isoproterenol, norepinephrine; phenylephrine (PE); 3 endothelin-1, insulin-like growth factor, epidermal growth factor (EGF); angiotensin II, neuregulin 1, transforming growth factor ␤ (TGF␤); interleukin 6 (IL6); fibroblast growth factor, FGF; cardiotrophin 1; leukemia inhibitory factor (LIF); stretch, brain naturetic peptide; atrial naturetic peptide) and seven phenotypic outputs (cell area and expression of six genes: sarcoplasmic reticulum ATPase, ␣-myosin heavy chain, ␤-myosin heavy chain, atrial naturetic peptide, brain naturetic peptide, and skeletal ␣-actin). The size of the model allowed for investigation of differential regulation of hypertrophy and crosstalk between pathways.…”

“…The cardiac hypertrophy response is managed by a dense web of signaling pathways with many species influencing cardiac myocyte growth (2). The complexity of this network has hindered the development of successful therapeutic strategies (3) and indicates the need for integrative systems approaches which can provide a global view of functional relationships in the network (4).…”

PKA phosphorylates histone deacetylase 5 and prevents its nuclear export, leading to the inhibition of gene transcription and cardiomyocyte hypertrophy

“…Cardiac fetal gene expression contributes to cardiac growth and hypertrophy (4,(31)(32)(33). A major feature of the hypertrophic response of cardiomyocytes is a pronounced sarcomeric rearrangement and enlargement of cell size that can be detected by immunostaining with α-actinin antibody.…”

NADPH oxidase-4 mediates protection against chronic load-induced stress in mouse hearts by enhancing angiogenesis

“…cardiac remodeling | hypoxia inducible factor | reactive oxygen species H eart failure results from disease stresses that chronically increase cardiac workload (1). The cardiac response to such insults involves remodeling of the cardiomyocytes, vasculature, and extracellular matrix that may initially be adaptive.…”

“…Persistent stress, however, results in contractile dysfunction, fibrosis, ventricular dilatation, and capillary rarefaction. Specific pathways are thought to drive adaptive vs. maladaptive features of remodeling (1)(2)(3).…”