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The term ventricular remodeling has been coined to describe the geometrical changes in size and shape of the left ventricle occurring after large myocardial ...
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Thromb Haemost 1999; 82 (Suppl.): 73–5

Ventricular Remodeling after Acute Myocardial Infarction R. Dietz, K. J. Osterziel, R. Willenbrock, D. C. Gulba, R. v. Harsdorf From the Franz-Volhard-Klinik, Charité, Medizinische Fakultät der Humboldt-Universität zu Berlin, Germany

Key words

Wall stress, angiotensin, endothelin, apoptosis Summary

The term ventricular remodeling has been coined to describe the geometrical changes in size and shape of the left ventricle occurring after large myocardial infarcts. We do not exactly know what initiates this process. Slipping of myofilaments following destruction of connective tissue – probably due to metalloproteinase activation – could be the initial event. As a consequence, wall stress is increased triggering deleterious adaptation processes, such as – intracardiac angiotensin II generation – cardiac endothelin formation and release – pro-apoptotic signals for cardiomyocytes – hypertrophic signals for fibroblasts and cardiomyocytes This cascade of events is not only observed in the process of remodeling following myocardial infarction but is also operating during the progression of heart failure. Therapeutic principles therefore are similar in both conditions: – reduction of wall stress (pharmacological or mechanical unloading of the heart) – blockade of angiotensin II generation or of AT1-receptors (ACEinhibitors or AT1 antagonists) – blockade of endothelin receptors (ETA-blockers) – blockade of adrenergic receptors (preferably 1-adrenergic receptor blockers). Better understanding of the molecular mechanisms of the remodeling process already has fueled the search for new therapeutic interventions (such as endothelin receptor blockers, aldosterone antagonists and growth hormone application). Continuous research in this field may be especially rewarding if we will succeed in identifying the very first step in the cascade. Introduction

Ventricular remodeling (1) is a term used to describe the progressive dilatation of the failing heart. Besides the geometrical changes in the shape of the heart it includes alterations in the functional capacity of the heart (2). Reduced systolic performance and increased diastolic

Correspondence to: R. Dietz, Charité, Medizinische Fakultät der HumboldtUniversität zu Berlin, Franz-Volhard-Klinik, Wiltbergstraße 50, 13125 Berlin, Germany – Tel.: +49 30 94172232; Fax: +49 30 9495960; E-mail: [email protected] Abbreviations: ACE: angiotensin converting enzyme; AT1-antagonist: angiotensin II antagonist (against receptor subtype 1); MI: myocardial infarction

stiffness are the consequences of changes at the level of tissue composition – i.e. an increase in interstitial cell matrix, and at the cellular level. Cardiomyocytes are not only thickened and elongated (3), but sometimes they silently vanish in severe heart failure in a process of programmed cell death – called apoptosis. On a molecular, subcellular level gene expression is switched to a more fetal phenotype in cardiomyocytes in the failing heart. This switch includes reexpression of atrial natriuretic peptide in the ventricles in combination with skeletal alpha-actin and collagen III. Following acute myocardial infarction the process of ventricular remodeling is triggered by a signal cascade which starts with the initial ischemic damage to the myocardium (4). If this has been large enough, wall stress will progressively increase and lead to the observed changes of the left ventricle in shape, function, tissue composition and gene expression (5, 6). Understanding of the sequence of these events helps to design strategies aimed to reverse the process of remodeling. Clinical and Experimental Findings

There are four levels of remodeling: 1. First Level of Remodeling: Shape of the Left Ventricle Successful early reperfusion of the infarct related artery either by thrombolysis or direct angioplasty are the best means to prevent remodeling following acute myocardial infarction. The time delay between onset of symptoms and reperfusion, however, often exceeds the time span during which jeopardized myocardium can be saved. Those patients then suffer from a large initial damage to the myocardium. Loss of systolic pump function in the infarcted area is usually compensated by a hypercontractile response in the noninfarcted areas. In addition, the increase in enddiastolic volume recruites inotropic forces according to the law of Frank-Starling. The price, however, for this short term compensation is enormous. Enlargement of the injured left ventricle following myocardial infarction results in an increase in wall stress. According to the law of Laplace, wall stress is defined as the product of intraventricular pressure times radius divided by wall thickness. A large infarct area will lead to progressive dilatation of the left ventricle (increase of radius in the Laplace formula). Increased enddiastolic volume and decreased compliance cause elevation of enddiastolic pressure, (increase of pressure in the Laplace formula). Expansion ot the left ventricle will lead to thinning of the ventricle walls (decrease in wall thickness in the Laplace formula). All three changes are contributing to a marked rise in wall stress which is regarded as the mechanistic principle that is translated into adaptive molecular responses. Taken together, these adaptations are not beneficial in long term: they will ultimately lead to an impairment of diastolic and systolic function as well as a further dilatation of the left ventricle. 73

Thromb Haemost 1999; 82 (Suppl.): 73–5

2. Second Level of Remodeling: Neurohormonal Regulation of Cardiac Function and Structure Survivors of large acute myocardial infarctions often exhibit symptoms of sympathetic stimulation: their heart rate is elevated, their skin is pale and wet. Measurement of noradrenaline and adrenaline reveal elevated plasma levels (8). In addition, the systemic and cardiac renin-angiotensin systems and the endothelin system are stimulated markedly. In parallel, the efficacy of the natriuretic peptide – system is blunted: in spite of elevated plasma concentrations of natriuretic peptides the neuroendocrine stimulation leads to an exaggerated vasoconstriction and retention of salt and water. Angiotensin II and endothelin do possess further characteristics as growth factors which initiate and perpetuate the remodeling process. 3. Third Level of Remodeling: Changes in Structure and Tissue Composition of the Failing Heart Microscopic evaluation of cardiac specimens during the process of remodeling show two fundamental changes: The first is a progressive loss of cardiac myocytes even in normally perfused areas along with an elongation and thickening of the remaining myocytes. The second change consists in a progressive increase in interstitial volume, both in cells and fibres. Functional consequences of a reduced contractile mass but increased connective tissue mass are a decreased systolic pump function and an impaired diastolic relaxation. 4. Fourth Level of Remodeling: Changes in Gene Expression in the Failing Heart Recent investigations have indicated that one characteristic feature of the failing heart is the induction of genes normally expressed exclusively during the prenatal myocardial organogenesis. Furthermore, programmed cell death has been observed in end stage heart failure (9). In general, programmed cell death (apoptosis) and cell proliferation are evolutionary concepts enabling organs to develop during the fetal period of life and to adjust to changes in the environment during their postnatal organogenesis. However, death and proliferation of cells would render a mechanically active organ like the heart extremely unstable putting its function to maintain circulation in our body at risk. Therefore, intracellular pathways which yet have to be identified initiate continuous suppression of apoptosis and proliferation of cardiomyocytes during the postnatal period of life. Although these pathways appear to be extremely effective, recent investigations in diseased myocardium revealed that they may be overturned and differentiation is reversed at least in part towards a fetal cardiac phenotype. However, at the moment the significance of these pathways regulating programmed cell death and cell cycle control of cardiomyocytes for the development of heart failure still is enigmatic. Recent investigations try to address whether the suppression or the induction of apoptosis are causally linked to the pathological phenotype in heart failure. We also need to understand what factors govern cell cycle control in terminally differentiated cardiomyocytes in order to understand the deleterious process of myocardial remodeling. Strategies to Reverse the Process of Remodeling

If it is true that the process of remodeling is caused by the following cascade of signalling: 74

increase in wall stress  intracardiac angiotensin II generation  endothelin release  cardiomyocyte growth and premature cell death  progressive impairment in diastolic and systolic pump function  “dying heart” then strategies may be developed which interrupt the signal cascade at different steps (10, 11). In principle, different attempts have already been proven beneficial whereas others are in an experimental phase. Strategies with Proven Benefit in either Clinical or Experimental Conditions Blockade of the renin-angiotensin-system today is the best validated pharmacological approach in preventing or ameliorating remodeling following myocardial infarction. Thousands of patients have been included in post-Mi ACE-inhibitor trials, the meta-analysis of which demonstrated a persistent effect on mortality reduction (12). Echocardiographic substudies have shown that ACE-inhibitors are able to prevent the progressive increase in enddiastolic and endsystolic volumes. From experimental data in the rat infarct model AT-1 antagonists appear to have the same potential of preventing remodeling (14). Clinical trials are underway to prove this assumption. Left ventricular hypertrophy has been used frequently as a marker of the change in phenotype which is associated with an increased risk in mortality. Angiotensin II has been regarded so far as a necessary and sufficient mediator of cardiac growth. There are, however, multiple switches that can be turned on to induce cardiac growth. Absence of angiotensin II dependent signaling does not prevent load induced ventricular hypertrophy. Presence of angiotensin II signaling alone may not be sufficient to induce significant hypertrophy without the simultaneous presence of endothelin. Endothelin antagonists administered in rats after ligation of the left anterior descending coronary artery not only reduced ventricular enlargement but also mortality. Betablocking agents in the postinfarction period are proven drugs to reduce mortality mainly by preventing sudden cardiac death (15). In addition, they have a small effect on ventricular dilatation during that phase. Experimental Strategies to Reduce or Reverse Remodeling Resting the failing heart is probably the most potent strategy for reverse remodeling. Left ventricular assist devices are powerful means to reduce wall stress and offer the opportunity for the failing heart to recover (16, 17). Recovery can be so effective that heart transplant candidates can be weaned in single cases from the assist device. The importance of the geometric shape for the performance of the failing heart is best demonstrated by the effects of the Batista operation (18). Partial left ventriculectomy (plus mitral reconstruction) reduces left ventricular volumes and wall stress and leads to an improvement in ejection fraction. This intervention may be taken as an example to support the following hypothesis: dilatation of the left ventricle comes first in the process of remodeling and the decrease in ejection fraction is the consequence. The Batista operation shrinks the left ventricle but improves systolic performance despite reduction of contractile mass! If the increase in wall stress would be the “primum movens” of remodeling it then would make sense to seek for non-invasive strategies to reduce wall stress. In dilated cardiomyopathy the subgroup of

Dietz et al.: Ventricular Remodeling

patients with the smallest relative wall thickness (and hence the highest wall stress) have the highest mortality. Epidemiologists and cardiologists have the strong belief that left ventricular hypertrophy should be treated aggressively –- which may be a fatal mistake in the situation of dying hearts. Induction, not regression of left ventricular hypertrophy may be the correct approach in these cases. Since we do not differentiate at the present time with our cardiac imaging techniques between the amount of contractile mass and interstitial mass contributing to hypertrophy we may have been mislead by the association of ventricular hypertrophy and mortality. If we would be able to selectively increase contractile mass without elevating the interstitial component, hypertrophy probably would be regarded as a valuable goal in the treatment of heart failure. This can be achieved by exogenous administration of growth hormone. Its application in the rat postinfarction model has been demonstrated to exert beneficial effects on remodeling and mortality (19). In man, its administration causes an increase in left ventricular mass (and reduction in wall stress) in patients with dilated cardiomyopathy (20). Whether this approach could represent a useful means in the clinical situation of progressive left ventricular dilatation post myocardial infarction remains to be tested.

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