Trends in Molecular Medicine
The molecular basis of myocardial hypertrophy and heart failure
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.
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