The molecular basis of myocardial hypertrophy and heart failure

https://doi.org/10.1016/S1471-4914(03)00114-XGet rights and content

Abstract

Heart failure (HF) is the inability of the heart to cope with the metabolic demands of the periphery. It is the common end-stage of many frequent cardiac diseases and is characterized by relentless progression. Mechanisms of progression include renal sodium and water retention, neurohumoral activation and alterations of the protein composition (gene programme) of the heart itself. In this review, we explain the often confusing terminology in the subject, briefly touch upon the peripheral mechanisms of HF, and then focus on the changes in the gene programme of the failing heart and the molecular mechanisms leading to them. Understanding the basic processes underlying HF will help uninitiated readers to gain insight into recent novel approaches to its treatment.

Section snippets

Relation of cardiac hypertrophy and HF

The terminology often seems confusing to the uninitiated and will therefore be addressed here. Clinically, the term ‘pathological hypertrophy’ is used loosely and refers to an abnormal increase in cardiac mass, usually stemming from an increase in the size of cardiac myocytes and an increase in number of the fibroblasts and other cells, such as those of the vasculature. Increased deposition of extracellular matrix (ECM) proteins, such as collagen and fibronectin, is also important. As a

HF versus the failing heart

Most of this review is devoted to the molecular composition and the cognate signalling mechanisms of the failing heart itself. However, this is a relatively new area of HF research 20, 21. By contrast, it has long been known that the syndrome of HF is characterized by activation of the renin–angiotensin–aldosterone system (RAAS), catecholamine secretion and cytokine elevation in the circulation. This situation, termed ‘neuroendocrine activation’, leads to progressive fluid retention (and thus

Molecular composition (‘phenotype’) of the failing heart

Here, we refer not to the infarcted zone of the heart, but to the previously healthy part, which then fails (e.g. after myocardial infarction). The clinical picture in hypertensive heart disease and failure is often compounded by coronary heart disease, but we will disregard this. Histologically, four features define the failing heart: (1) myocyte hypertrophy; (2) fibrosis; (3) ‘slippage’ of the previously orderly aligned myocytes, which presumably leads to inefficient contraction; and (4)

Molecular mechanisms leading to HF

One of the major questions in HF (and hypertrophy) research is the mechanism by which cardiac cells sense stretch, and much progress has been made in recent years. The structure into which contractile proteins insert is known as the Z-line, and it is here that (at least one of possibly several) stretch sensing mechanisms have been recently localized [12]. Integrins link the outside and inside of the cell and are also localized close to the Z-line, as are members of the dystrophin complex. The

Outlook

This review is meant to be somewhat simplified for the uninitiated reader, but it should be clear that the molecular alterations in HF and the mechanisms leading to them form a fascinating and complex array. In the past ten years, there has been a 46% reduction in mortality resulting from HF, but HF is still one of the most frequent causes of death in the western world [2]. At the molecular level, inhibition of the activated neurohormonal–cytokine systems in HF seems to be a promising approach.

Acknowledgements

This work was made possible through an international appointee grant from the Medical Research Council (UK) and the ‘German Research Foundation’, SFB 355, to L.N., and through support from the ‘Ernst und Berta Grimmke Stiftung’ (Germany) to O.R. We thank K. Schuh for critical reading of the manuscript.

References (94)

  • C. Delcayre et al.

    Molecular mechanisms of myocardial remodeling. The role of aldosterone

    J. Mol. Cell. Cardiol.

    (2002)
  • M.A. Hefti

    Signaling pathways in cardiac myocyte hypertrophy

    J. Mol. Cell. Cardiol.

    (1997)
  • T.P. Garrington et al.

    Organization and regulation of mitogen-activated protein kinase signaling pathways

    Curr. Opin. Cell Biol.

    (1999)
  • A. Paul

    Stress-activated protein kinases: activation, regulation and function

    Cell. Signal.

    (1997)
  • G.R. Crabtree et al.

    NFAT signaling: choreographing the social lives of cells

    Cell

    (2002)
  • J.D. Molkentin

    A calcineurin-dependent transcriptional pathway for cardiac hypertrophy

    Cell

    (1998)
  • B.A. Rothermel

    The role of modulatory calcineurin-interacting proteins in calcineurin signaling

    Trends Cardiovasc. Med.

    (2003)
  • C.L. Zhang

    Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy

    Cell

    (2002)
  • T. Pelzer

    Estrogen effects in the myocardium: inhibition of NF-κB DNA binding by estrogen receptor-α and -β

    Biochem. Biophys. Res. Commun.

    (2001)
  • T. Pelzer

    17β-estradiol prevents programmed cell death in cardiac myocytes

    Biochem. Biophys. Res. Commun.

    (2000)
  • K.R. Chien

    Stress pathways and heart failure

    Cell

    (1999)
  • N. Frey et al.

    Cardiac hypertrophy: the good, the bad, and the ugly

    Annu. Rev. Physiol.

    (2003)
  • E. Braunwald et al.

    Congestive heart failure: fifty years of progress

    Circulation

    (2000)
  • J.J. Hunter et al.

    Signaling pathways for cardiac hypertrophy and failure

    N. Engl. J. Med.

    (1999)
  • D.M. Lloyd-Jones

    Lifetime risk for developing congestive heart failure: the Framingham Heart Study

    Circulation

    (2002)
  • K. Schwartz et al.

    Molecular and cellular biology of heart failure

    Curr. Opin. Cardiol.

    (1996)
  • B.J. Maron

    Epidemiology of hypertrophic cardiomyopathy-related death: revisited in a large non-referral-based patient population

    Circulation

    (2000)
  • R. Roberts et al.

    Myocardial diseases

    Circulation

    (2000)
  • L. Eckardt

    Arrhythmias in heart failure: current concepts of mechanisms and therapy

    J. Cardiovasc. Electrophysiol.

    (2000)
  • J.M. Schnee et al.

    Angiotensin II, adhesion, and cardiac fibrosis

    Cardiovasc. Res.

    (2000)
  • T. Force

    Stretch-activated pathways and left ventricular remodeling

    J. Card. Fail.

    (2002)
  • M. Brancaccio

    Melusin, a muscle-specific integrin β1-interacting protein, is required to prevent cardiac failure in response to chronic pressure overload

    Nat. Med.

    (2003)
  • D. Fatkin et al.

    Molecular mechanisms of inherited cardiomyopathies

    Physiol. Rev.

    (2002)
  • B. Swynghedauw

    Molecular mechanisms of myocardial remodeling

    Physiol. Rev.

    (1999)
  • T. Senbonmatsu

    Evidence for angiotensin II type 2 receptor-mediated cardiac myocyte enlargement during in vivo pressure overload

    J. Clin. Invest.

    (2000)
  • A. Godecke

    Coronary hemodynamics in endothelial NO synthase knockout mice

    Circ. Res.

    (1998)
  • G. Esposito

    Genetic alterations that inhibit in vivo pressure-overload hypertrophy prevent cardiac dysfunction despite increased wall stress

    Circulation

    (2002)
  • P. Anversa et al.

    Myocyte renewal and ventricular remodelling

    Nature

    (2002)
  • A.M. Lompre

    Myosin isoenzyme redistribution in chronic heart overload

    Nature

    (1979)
  • D. Siehl

    Faster protein and ribosome synthesis in thyroxine-induced hypertrophy of rat heart

    Am. J. Physiol.

    (1985)
  • P.A. Poole-Wilson

    Treatment of acute heart failure: out with the old, in with the new

    J. Am. Med. Assoc.

    (2002)
  • R. Corti

    Vasopeptidase inhibitors: a new therapeutic concept in cardiovascular disease?

    Circulation

    (2001)
  • P. Anversa et al.

    Myocyte cell death in the diseased heart

    Circ. Res.

    (1998)
  • A. Elsasser

    The role of apoptosis in myocardial ischemia: a critical appraisal

    Basic Res. Cardiol.

    (2001)
  • H.E. Morgan

    Biochemical mechanisms of cardiac hypertrophy

    Annu. Rev. Physiol.

    (1987)
  • J.J. Hwang

    Genomics and the pathophysiology of heart failure

    Curr. Cardiol Rep.

    (2001)
  • K. Schwartz

    The molecular biology of heart failure

    J. Am. Coll. Cardiol.

    (1993)
  • Cited by (71)

    • Protective effects of dioscin against isoproterenol-induced cardiac hypertrophy via adjusting PKCε/ERK-mediated oxidative stress

      2021, European Journal of Pharmacology
      Citation Excerpt :

      However, the protective effect of dioscin on CH induced by ISO has not been reported, it is worthy of further study in the treatment of CH. The pathogenesis of CH is complex, which may be associated with oxidative stress, inflammation, calcium overload and autophagy (Ritter and Neyses, 2003). There are evidences that oxidative stress can lead to cardiovascular dysfunction associated with hyperlipidemia, hypertension, ischemic heart disease and chronic heart failure (Taniyama and Griendling, 2003; Rey and Pagano, 2002).

    • Cardiovascular outcomes related to social defeat stress: New insights from resilient and susceptible rats

      2019, Neurobiology of Stress
      Citation Excerpt :

      If we consider the increased heart weight in susceptible animals as a sign of cardiac hypertrophy, it should be related to increased sympathetic tone to the heart. The pathogenesis of cardiac hypertrophy involves diverse factors, including increased sympathetic activity (Samak et al., 2016; Yamazaki and Yazaki, 2000), and molecular alterations in cardiac hypertrophy are considered as the first step in the development of heart failure (Ritter and Neyses, 2003). On the other hand, it is also an important and reversible adaptive response during pregnancy and to exercise in athletes.

    • Plantamajoside attenuates isoproterenol-induced cardiac hypertrophy associated with the HDAC2 and AKT/ GSK-3β signaling pathway

      2019, Chemico-Biological Interactions
      Citation Excerpt :

      Physiological cardiac hypertrophy is characterized by an increase in the total amount of cardiac muscle mass and myocardial contractility. Although cardiac hypertrophy may initially be a compensatory mechanism to maintain normal blood circulation, continuous hypertrophy will develop into pathological cardiac hypertrophy [1], which is accompanied by obvious disorder of the cardiac myocytes arrangement, fibrosis, myocytes apoptosis, and re-expression of embryonic genes (ANP, BNP, β-MHC, α-skeletal actin) [2], and persistent cardiac hypertrophy may lead to myocardial infarction, arrhythmia, heart failure and sudden death [3,4]. Although cardiac hypertrophy has been known for more than a century, its underlying mechanism is still not fully understood [5], and a multitude of extracellular factors and signaling pathways are involved according to previous studies [6].

    • Transfection by eukaryotic expression vector pcDNA3-HERG inhibits the cultured neonatal rabbit ventricular myocyte hypertrophy induced by phenylephrine

      2012, Cardiovascular Pathology
      Citation Excerpt :

      The activation of the sympathetic nervous system plays a major role in the whole-body neuroregulation of hypertrophic remodeling. In particular, adrenergic signals stimulate cardiac hypertrophy mainly through the α1 adrenoceptor subgroup, whereas β-receptors participate more in the regulation of cardiac function [9]. Stimulation of α1 adrenoceptors can prolong APD in rat and rabbit ventricular myocytes by alterations of many ionic currents including the reductions in Ito and the delayed rectifier potassium current (IK) [8,10].

    • Effects of Grayanotoxin-III on different cell lines: in vitro ischemia model

      2023, International Journal of Secondary Metabolite
    View all citing articles on Scopus
    View full text