PMC

Candidate miRNAs with suggested roles in the cardiac remodelling process are depicted with respect to the how they might influence the process of LV remodelling. (From Topkara VK, Mann DL: Clinical applications of miRNAs in cardiac remodeling and heart failure. Personalized Medicine 2010;7:531–548).

Major pumps, channels and regulatory proteins involved in excitation-contraction coupling in the cardiac myocyte. Calcium (Ca) influx through L-type channels triggers the release of further Ca from the sarcoplasmic reticulum (SR) via ryanodine receptor channels (RyR). In addition to Ca-myofilament interaction (which regulates contraction and relaxation), Ca also regulates mitochondrial functions and may have effects in other organelles such as the nucleus. Calcium re-uptake into the SR occurs via the calcium ATPase pump (SERCA), which is regulated by phospholamban. Other membrane pumps and channels also contribute to Ca homeostasis. Dysfunction at different levels of this process contributes to contractile dysfunction in the failing myocyte and the molecular abnormalities underlying this dysfunction may define potential therapeutic targets. (Adapted from Mann DL, Pathophysiology of Heart Failure. In Bonow RO, Mann DL, Zipes DP, Libby P *eds+: Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine, 9^th ed, pp ????, 2010).

Application of a systems biology approach to understanding the pathogenesis of heart failure. A, Systems biology involves a series of steps traditionally beginning with highly sophisticated characterisation of genomic, transcriptomic, proteomic, and metabolomic data sets, which can then be analyzed using a variety of bioinformatic approaches. Systems biology places emphasis on defining interactions, delineating networks linking proteins, genes or metabolites, and describing functional units or sets to provide testable mechanistic models of clinical phenotypes. B, Visual illustration of a simple “scale free” gene network, which is comprised of nodes (circles) with a large number of links or “edges” (depicted by lines) which represent the interaction (activation or suppression) between the nodes. C, Visual illustration of a complex scale free network, with the majority of nodes having one or two links and a few nodes (illustrated in red) having a large number of links. Nodes with a high degree of connectivity are referred to as “hubs.” The high degree of connectivity guarantees that the system is fully connected. (Adapted from Adams KF. Systems biology and heart failure: concepts, methods, and potential implications. Heart Fail Rev 2010;15:371–98).

Multiple pathways can regulate cardiomyocyte growth, acting through a complex network of intracellular signalling cascades. Agonists for α-adrenergic, angiotensin, and endothelin receptors couple to phospholipase C (PLC) and calcium influx channels (CC) by way of G-proteins (Gα and Gγ). Activation of PLC results in the generation of two second messengers, inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 causes the release of calcium from intracellular stores, and DAG activates protein kinase C (PKC). Changes in intracellular calcium stores can activate calcium-calmodulin-dependent kinases (CaCMK), as well as calcineurin, which affect gene expression in multiple ways. The modulation of other membrane transporters (such as the Na⁺-H⁺ exchanger which regulates cellular pH) and the activation of mitogen-activated protein kinase (MAPK) cascades are also involved. Histone deacetylase complexes (HDACs) are emerging as important negative regulators of genes involved in cardiac hypertrophy. Cytokines and peptide growth factors can be elaborated by various cells within the heart and may act in an autocrine or paracrine manner, generally via tyrosine kinase (TK) receptors that are coupled to downstream protein kinase signalling cascades cascade. Mechanical forces can also affect hypertrophy through several pathways, including direct effects at the level of the sarcomere, alterations in matrix-integrin interactions and the autocrine action of released agonists such as angiotensin. Both nitric oxide and reactive oxygen species are capable of modulating distinct signalling pathways within the cell, either in a negative or positive fashion depending upon circumstances. The net effects of such intracellular signalling include myocyte hypertrophy, changes in contractile function and altered cell viability. (Adapted from Mann DL, Pathophysiology of Heart Failure. In Bonow RO, Mann DL, Zipes DP, Libby P [eds]: Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine, 9^th ed, pp ????, 2010).