What Causes a Broken Heart-Molecular Insights into Heart Failure

Seán P. Barry, Paul A. Townsend

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Our understanding of the molecular processes which regulate cardiac function has grown immeasurably in recent years. Even with the advent of β-blockers, angiotensin inhibitors and calcium modulating agents, heart failure (HF) still remains a seriously debilitating and life-threatening condition. Here, we review the molecular changes which occur in the heart in response to increased load and the pathways which control cardiac hypertrophy, calcium homeostasis, and immune activation during HF. These can occur as a result of genetic mutation in the case of hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) or as a result of ischemic or hypertensive heart disease. In the majority of cases, calcineurin and CaMK respond to dysregulated calcium signaling and adrenergic drive is increased, each of which has a role to play in controlling blood pressure, heart rate, and left ventricular function. Many major pathways for pathological remodeling converge on a set of transcriptional regulators such as myocyte enhancer factor 2 (MEF2), nuclear factors of activated T cells (NFAT), and GATA4 and these are opposed by the action of the natriuretic peptides ANP and BNP. Epigenetic modification has emerged in recent years as a major influence cardiac physiology and histone acetyl transferases (HATs) and histone deacetylases (HDACs) are now known to both induce and antagonize hypertrophic growth. The newly emerging roles of microRNAs in regulating left ventricular dysfunction and fibrosis also has great potential for novel therapeutic intervention. Finally, we discuss the role of the immune system in mediating left ventricular dysfunction and fibrosis and ways this can be targeted in the setting of viral myocarditis. © 2010 Elsevier Inc.
    Original languageEnglish
    Pages (from-to)113-179
    Number of pages66
    JournalInternational Review of Cell and Molecular Biology
    Volume284
    Issue numberC
    DOIs
    Publication statusPublished - 2010

    Keywords

    • Ca+ signaling
    • Carciac hypertrophy
    • Cardiac function
    • Heart failure
    • Myocarditis
    • Natriuretic peptides

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