- Email: [email protected]
Ventricular remodeling
Crit Care Nurs Clin N Am 15 (2003) 407 – 411
Ventricular remodeling Sara Paul, MSN, RN, FNP* Hickory Cardiology Associates, 1771 Tate Blvd. SE, Suite 201, Hickory, NC 28602, USA
Heart failure was at one time thought to be simply a problem of poor ventricular contractility leading to depressed hemodynamics. During the last 20 years, however, researchers have found that cardiac cells become altered through a complex cascade of events long before hemodynamic compromise becomes apparent. The term ventricular remodeling is used to describe the change in ventricular size, shape, and function that occurs over time in response to an index event. Neurohormone and cytokine activation enhance the remodeling process after the index event and promote progression of heart failure by stimulating further changes in the myocytes. New information continues to surface as researchers explore the pathophysiology of cardiac myocytes in heart failure in animal models, but knowledge about ventricular remodeling in humans is relatively sparse. It is difficult to separate discussion of neurohormones from the pathophysiology of ventricular remodeling, but other articles in this issue describe the neurohormonal changes that occur with heart failure. This article provides an overview of the remodeling process as it is currently known and defines some of the terminology used when describing this pathophysiologic process.
The index event Quite often, an index event in the heart precedes a period of asymptomatic left ventricular dysfunction before signs and symptoms of heart failure become
evident [1,2]. Examples of index events preceding left ventricular remodeling include Acute myocardial infarction (MI) Genetic mutation Myocardial inflammation from acute myocarditis Systemic hypertension Valvular heart disease Congenital heart disease Severe chronic obstructive lung disease Untreated hyperthyroidism The index event may be an acute injury, as in MI, or it may be a progressive event, as in myocardial inflammation from acute myocarditis. It may even develop gradually over time, as in systemic hypertension and pressure overload or valvular insufficiency and volume overload. In many cases, the index event is silent and is never identified, as in idiopathic dilated cardiomyopathy. In the United States, coronary artery disease or the combination of systemic hypertension, left ventricular hypertrophy, and diabetes mellitus are the most common culprits leading to heart failure [3,4]. The transition from an index event to overt heart failure is not well understood, but the different causes of cardiac remodeling share common molecular, biochemical, and mechanical pathways. Remodeling after MI is discussed in detail later, but similar cellular mechanisms are thought to be common to all causes of heart failure.
Ventricular remodeling
* 1681 8th Street Drive North West, Hickory, NC 28601. E-mail address: [email protected]
After MI, left ventricular remodeling begins within the first few hours and progresses over time for weeks or months [5 – 7]. Myocyte necrosis and the
0899-5885/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0899-5885(02)00089-8
408
S. Paul / Crit Care Nurs Clin N Am 15 (2003) 407–411
resultant stress on the myocardium trigger a cascade of biochemical intracellular signals that initiate a compensatory response to the event. Initially, this response preserves cardiac output in the presence of damaged myocardium. When the intracellular signals continue beyond the compensatory phase, the myocardium begins to remodel, and left ventricular function eventually deteriorates (Fig. 1). The early phase of ventricular remodeling (within 72 hours of MI) involves expansion of the infarct zone, possibly resulting in ventricular rupture or aneurysm formation [8]. Within 3 hours of MI, the infarcted area expands and thins because of degradation (breakdown) of the collagen struts that hold myocytes together in alignment [9]. Experimentally, myocardial collagenases known as matrix metalloproteinases (MMPs) are activated in response to certain signals. These MMPs are secreted into the extracellular matrix and are probably responsible for disrupting the collagen strut network that normally weaves the myocytes together [10,11]. The myocytes undergo slippage and lose their normal parallel alignment when the collagen no longer binds them together. Additionally, the capillaries that were held close to the myocytes by the collagen become distanced from the cardiac cells, making the transfer of oxygen and nutrients difficult. Macrophages, monocytes, and neutrophils migrate to the infarct zone and initiate neurohormonal activation, localizing the inflammatory response. Slippage of the myocytes causes thinning and dilatation of the myocardial wall at the site of the infarct. Myocardial diastolic and systolic wall stress increases because of the dilatation, and this increased stress serves as a powerful stimulus
for hypertrophy in the remote noninfarcted myocardium [12,13]. An analogy to clarify this concept is holding a rubber band slightly expanded around one’s fingers. This position simulates normal myocardial stretch. When the rubber band is stretched out by moving one’s fingers farther apart, the rubber band has more tension and becomes taut. The farther one stretches the rubber band, the more stress is put on it. The same is true of the myocardium: when the infarct area dilates, it causes the entire ventricle to stretch, creating stress in the walls of the ventricle. The larger the infarct area, the greater the dilatation and systolic and diastolic wall stress [14]. As the myocytes stretch, local norepinephrine activity and angiotensin and endothelin release are increased. This increase stimulates expression of altered proteins and induces more myocyte hypertrophy. Myocytes may become elongated or hypertrophied, depending on the synthesis of new contractile proteins and the assembly of new sarcomeres. The pattern in which these sarcomeres are laid down determines whether the myocytes elongate or increase their diameter [15]. Angiotensin II production is enhanced locally in the noninfarcted myocardium, and this enhanced production is a likely stimulus for hypertrophy [16]. Initially, this hypertrophy is an adaptive response to preserve stroke volume [13]; however, the end result is further deterioration in cardiac performance and increased neurohormonal activation [17]. Mechanical deformation of the myocyte membrane, as seen with increased left ventricular filling pressure, is associated with protein synthesis and enlargement of the cardiac myocytes [18,19]. Neuro-
Fig.1. Cardiac remodeling over time in infarct and noninfarct regions after transmural infarction. (From Rumberger JA. Ventricular dilatation and remodeling after myocardial infarction. Mayo Clin Proc 1994;69:664 – 74, with permission.)
S. Paul / Crit Care Nurs Clin N Am 15 (2003) 407–411
hormonal factors such as angiotensin II, norepinephrine, and endothelin are associated with an increase in cardiac cell size and hypertrophy [20]. The presence of angiotensin II, tumor necrosis factor-a (TNF-a), endothelin-1, and catecholamines seems also to be associated with an increase in MMPs [21]. Increased aldosterone production in response to increased levels of angiotensin II stimulates collagen synthesis by myocardial fibroblasts and contributes to fibrosis of the infarcted and noninfarcted regions of the ventricle [22]. Cytokines are peptides, distinct from neurotransmitters or neurohormones, that are released locally in response to injury, promoting inflammation. Cytokines such as TNF-a are released from the heart or from inflammatory cells that have migrated into the infarct zone and are presumed to contribute to hypertrophy and apoptosis. Circulating levels of TNF-a and other inflammatory cytokines are elevated in heart failure patients and can regulate growth and gene expression in cardiac myocytes and other cells in the myocardium [23,24]. Apoptosis is a term used to describe a genetically programmed, energy-requiring process of cell death, distinct from necrosis, in which cells involute, condense, and shrink. The cells fragment into smaller apoptotic bodies that are efficiently removed by neighboring cells or phagocytes. Rapid removal of the contained apoptotic cells prevents the influx of inflammatory cells that typically cause significant collateral damage to surrounding normal tissues. This process is likened to dead leaves falling off a tree and is a defense mechanism to rid an organ of damaged or infected cells without the inflammatory process. Endothelin-1 is a peptide that plays a minor role in normal cardiovascular function but is elevated in heart failure patients and assumes a major role in the regulation of hemodynamics, vascular and myocardial function, and remodeling. It has potent vasoconstrictor properties, stimulates neurohormonal activation, and contributes to remodeling through pathologic hypertrophy and myocardial fibrosis. Additionally, endothelin can be proinflammatory and proarrhythmic. As remodeling progresses, the extracellular matrix forms a collagen scar at the infarct site to stabilize the wall stress and prevent further deformation [5,25]. Within 1 month after an MI, the necrotic myocytes in the infarct zone are entirely replaced by fibrous tissue [9]. Collagen accumulation occurs in noninfarcted myocardium as well. This matrix accumulates in the interstitial spaces, and diastolic function is impaired as the ventricular chamber becomes stiff. As the heart undergoes remodeling, it becomes
409
less elliptical and more spherical in shape [26]. Eventually, systolic performance becomes compromised, and clinical heart failure is evident [20]. The greater the extent of remodeling, the poorer the patient’s prognosis [17].
Factors influencing cardiac remodeling Hypertension Endogenous vasoconstrictors are normally offset by endogenous vasodilators. In heart failure, however, vasoconstrictors seem to predominate over vasodilators, and the forces become unbalanced. Vasoconstriction is enhanced by amplification of neurohormones such as angiotensin II, aldosterone, and endothelin-1 during the remodeling process. Elevation of blood pressure can increase left ventricular pressure and exacerbate infarct expansion and thinning. Patency of infarct-related artery Researchers have found that patients with collateral circulation and those with subtotal occlusion do not undergo as much left ventricular dilatation as those with similar-sized infarctions caused by complete coronary occlusion. The degree of coronary perfusion was found to be a more important predictor of volume change within the ventricle than the actual size of the infarct [27]. Reperfusion may salvage endocardial tissue and restore stunned myocardium in the infarct border zone. Location and size of infarct Infarct size and location determine the likelihood of late remodeling ( > 72 hours after the infarct). Additionally, infarct expansion occurs more often with left anterior descending coronary artery occlusion than with right coronary artery occlusion and is associated with large transmural infarcts [28]. Neurohormone activation Neurohormonal activation mediates compensatory changes in the heart in response to decreased cardiac output with heart failure. Angiotensin II, norepinephrine, and vasopressin exert effects on the myocytes to potentiate the remodeling process. These neurohormones, along with cytokines and endothelin, promote the progression of heart failure and the remodeling process.
410
S. Paul / Crit Care Nurs Clin N Am 15 (2003) 407–411
Summary Ventricular remodeling is an extremely complicated process that is not well understood. There seem to be multiple feedback loops that respond to mechanical events as well as to neurohormonal stimulation, cytokine release, and other, yet unidentified, agents. The progression of ventricular remodeling after the index event includes Myocyte slippage and thinning of infarct area, chamber dilatation Fibrosis and scar formation Collagen strut dissolution and excessive accumulation of interstitial matrix Increased wall stress Myocyte hypertrophy Neurohormonal activation Cytokine release Ongoing myocyte hypertrophy Cell apoptosis and necrosis Continued deterioration of cardiac function It is impossible to place the sequence of events in order, because the multiple feedback systems create a complex interactive process. A basic awareness of the pathophysiology of ventricular remodeling can aid in understanding current and future treatments for heart failure. It is clear that therapeutic interventions solely aimed at improving cardiac pump function do not slow the progression of heart failure or reduce mortality [29 – 31]. Drugs that block the neuroendocrine contribution to the remodeling process have been shown to have a greater impact [32]. Current therapies with angiotensin-converting enzyme inhibition, b blockade, and aldosterone antagonism are associated with significant reductions in morbidity and mortality in heart failure. Other therapeutic strategies suggested by knowledge of remodeling mechanisms, such as drugs to block cytokines, endothelins, and MMPs, may offer further benefit to patients with heart failure in the future.
References [1] Vasam R, Larson M, Benjamin E, et al. Left ventricular dilatation and the risk of congestive heart failure in people without myocardial infarction. N Engl J Med 1997;336:1350 – 5. [2] Thomas K, Redfield M. Asymptomatic left ventricular dysfunction. Heart Fail Rev 1997;2:11 – 22. [3] Kannel W, Belanger A. Epidemiology of heart failure. Am Heart J 1991;121:951 – 7.
[4] Smith W. Epidemiology of congestive heart failure. Am J Cardiol 1985;55:3A – 8A. [5] Sutton MSJ, Sharpe N. Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation 2000;101:2981 – 8. [6] Giannuzzi P, Temporelli P, Bosimini E, et al. Heterogeneity of left ventricular remodeling after acute myocardial infarction. Am Heart J 2001;141:131. [7] Korup E, Dalsgaard D, Nyvad O, et al. Comparisons of degrees of left ventricular dilation within 3 hours and up to 6 days after onset of first acute myocardial infarction. Am J Cardiol 1997;80:449. [8] Erlebacher J, Weiss J, Weisfeldt M, et al. Early dilation of the infarcted segment in acute transmural myocardial infarction: role of infarct expansion in acute left ventricular enlargement. J Am Coll Cardiol 1984; 4:201 – 8. [9] Cleutjens J, Kandala J, Guarda E, et al. Regulation of collagen degradation in the rat myocardium after infarction. J Mol Cell Cardiol 1995;27:1281 – 92. [10] Spinale F, Coker M, Thomas C, et al. Time-dependent changes in matrix metalloproteinase activity and expression during the progression of congestive heart failure. Circ Res 1998;82:482 – 95. [11] Dollery C, McEwan J, Henney A. Matrix metalloproteinases and cardiovascular disease. Circ Res 1995; 77:863 – 8. [12] Sadoshima J, Jahn L, Takahashi T, et al. Molecular characterization of the stretch-induced adaptation of cultured cardiac cells: an in vitro model of load-induced cardiac hypertrophy. J Biol Chem 1992;267:10551 – 60. [13] Lew W, Chen Z, Guth B, et al. Mechanisms of augmented segment shortening in nonischemic areas during acute ischemia of the canine left ventricle. Circ Res 1985;56:351 – 8. [14] Anversa P, Olivetti G, Capasso J. Cellular basis of ventricular remodeling after myocardial infarction. Am J Cardiol 1991;68:7D – 16D. [15] Francis G, McDonald K. Left ventricular hypertrophy: an initial response to myocardial injury. Am J Cardiol 1992;69:3G – 6G. [16] Lindpaintner K, Lu W, Neidermajer N, et al. Selective activation of cardiac angiotensinogen gene expression in post-infarction ventricular remodeling in the rat. J Mol Cell Cardiol 1993;25:133 – 43. [17] Cohn J, Ferrari R, Sharpe N. Cardiac remodeling – concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. J Am Coll Cardiol 2000;35:569 – 82. [18] Schneider M, Roberts R, Parker T. Modulation of cardiac genes by mechanical stress: the oncogene signaling hypothesis. Mol Biol Med 1991;8:167 – 83. [19] Komuro I, Kaida T, Shibazake Y, et al. Stretching cardiac myocytes stimulates proto-oncogene expression. J Biol Chem 1990;265:3595 – 8. [20] Francis G. Pathophysiology of chronic heart failure. Am J Med 2001;110:37S – 46S. [21] Nagase H. Activation mechanisms of matrix metalloproteinases. Biol Chem 1997;378:151 – 60.
S. Paul / Crit Care Nurs Clin N Am 15 (2003) 407–411 [22] Brilla C, Zhou G, Matsubara L, et al. Collagen metabolism in cultured adult rat cardiac fibroblasts: response to angiotensin II and aldosterone. J Mol Cell Immunol 1994;26:809 – 20. [23] Torre-Amione G, Kapadia S, Benedict C, et al. Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol 1996;27:1206. [24] Levine B, Kalman J, Mayer L, et al. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 1990;323:236. [25] Cohen M, Yang X, Neumann T, et al. Favorable remodeling enhances recovery of regional myocardial function in the weeks after infarction in ischemically preconditioned hearts. Circulation 2000;102:579. [26] Mitchell G, Lamas G, Vaughan D, et al. Left ventricular remodeling in the year after first anterior myocardial infarction: a quantitative analysis of contractile segment lengths and ventricular shape. J Am Coll Cardiol 1992;19:1136.
411
[27] Jeremy R, Hackworthy R, Bautovich G, et al. Infarct artery perfusion and changes in left ventricular volume in the month after acute myocardial infarction. J Am Coll Cardiol 1987;9:989 – 95. [28] Pirolo J, Hutchins G, Moore G. Infarct expansion: pathologic analysis of 204 patients with a single myocardial infarct. J Am Coll Cardiol 1986;7:349 – 54. [29] Massie B, Fisher S, Deedwania P, et al. Effect of amiodarone on clinical status and left ventricular function in patients with congestive heart failure (CHF-STAT Investigation). Circulation 1996;93:2128 – 34. [30] The Digitalis Investigation Group. The effects of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997;336:525 – 33. [31] Packer M, Carver J, Rodeheffer R, et al. Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med 1991;325:1468 – 75. [32] Packer M. Evolution of the neurohormonal hypothesis to explain the progression of chronic heart failure. Eur Heart J 1995;16(Suppl F):4 – 6.
Ventricular remodeling Sara Paul, MSN, RN, FNP* Hickory Cardiology Associates, 1771 Tate Blvd. SE, Suite 201, Hickory, NC 28602, USA
Heart failure was at one time thought to be simply a problem of poor ventricular contractility leading to depressed hemodynamics. During the last 20 years, however, researchers have found that cardiac cells become altered through a complex cascade of events long before hemodynamic compromise becomes apparent. The term ventricular remodeling is used to describe the change in ventricular size, shape, and function that occurs over time in response to an index event. Neurohormone and cytokine activation enhance the remodeling process after the index event and promote progression of heart failure by stimulating further changes in the myocytes. New information continues to surface as researchers explore the pathophysiology of cardiac myocytes in heart failure in animal models, but knowledge about ventricular remodeling in humans is relatively sparse. It is difficult to separate discussion of neurohormones from the pathophysiology of ventricular remodeling, but other articles in this issue describe the neurohormonal changes that occur with heart failure. This article provides an overview of the remodeling process as it is currently known and defines some of the terminology used when describing this pathophysiologic process.
The index event Quite often, an index event in the heart precedes a period of asymptomatic left ventricular dysfunction before signs and symptoms of heart failure become
evident [1,2]. Examples of index events preceding left ventricular remodeling include Acute myocardial infarction (MI) Genetic mutation Myocardial inflammation from acute myocarditis Systemic hypertension Valvular heart disease Congenital heart disease Severe chronic obstructive lung disease Untreated hyperthyroidism The index event may be an acute injury, as in MI, or it may be a progressive event, as in myocardial inflammation from acute myocarditis. It may even develop gradually over time, as in systemic hypertension and pressure overload or valvular insufficiency and volume overload. In many cases, the index event is silent and is never identified, as in idiopathic dilated cardiomyopathy. In the United States, coronary artery disease or the combination of systemic hypertension, left ventricular hypertrophy, and diabetes mellitus are the most common culprits leading to heart failure [3,4]. The transition from an index event to overt heart failure is not well understood, but the different causes of cardiac remodeling share common molecular, biochemical, and mechanical pathways. Remodeling after MI is discussed in detail later, but similar cellular mechanisms are thought to be common to all causes of heart failure.
Ventricular remodeling
* 1681 8th Street Drive North West, Hickory, NC 28601. E-mail address: [email protected]
After MI, left ventricular remodeling begins within the first few hours and progresses over time for weeks or months [5 – 7]. Myocyte necrosis and the
0899-5885/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0899-5885(02)00089-8
408
S. Paul / Crit Care Nurs Clin N Am 15 (2003) 407–411
resultant stress on the myocardium trigger a cascade of biochemical intracellular signals that initiate a compensatory response to the event. Initially, this response preserves cardiac output in the presence of damaged myocardium. When the intracellular signals continue beyond the compensatory phase, the myocardium begins to remodel, and left ventricular function eventually deteriorates (Fig. 1). The early phase of ventricular remodeling (within 72 hours of MI) involves expansion of the infarct zone, possibly resulting in ventricular rupture or aneurysm formation [8]. Within 3 hours of MI, the infarcted area expands and thins because of degradation (breakdown) of the collagen struts that hold myocytes together in alignment [9]. Experimentally, myocardial collagenases known as matrix metalloproteinases (MMPs) are activated in response to certain signals. These MMPs are secreted into the extracellular matrix and are probably responsible for disrupting the collagen strut network that normally weaves the myocytes together [10,11]. The myocytes undergo slippage and lose their normal parallel alignment when the collagen no longer binds them together. Additionally, the capillaries that were held close to the myocytes by the collagen become distanced from the cardiac cells, making the transfer of oxygen and nutrients difficult. Macrophages, monocytes, and neutrophils migrate to the infarct zone and initiate neurohormonal activation, localizing the inflammatory response. Slippage of the myocytes causes thinning and dilatation of the myocardial wall at the site of the infarct. Myocardial diastolic and systolic wall stress increases because of the dilatation, and this increased stress serves as a powerful stimulus
for hypertrophy in the remote noninfarcted myocardium [12,13]. An analogy to clarify this concept is holding a rubber band slightly expanded around one’s fingers. This position simulates normal myocardial stretch. When the rubber band is stretched out by moving one’s fingers farther apart, the rubber band has more tension and becomes taut. The farther one stretches the rubber band, the more stress is put on it. The same is true of the myocardium: when the infarct area dilates, it causes the entire ventricle to stretch, creating stress in the walls of the ventricle. The larger the infarct area, the greater the dilatation and systolic and diastolic wall stress [14]. As the myocytes stretch, local norepinephrine activity and angiotensin and endothelin release are increased. This increase stimulates expression of altered proteins and induces more myocyte hypertrophy. Myocytes may become elongated or hypertrophied, depending on the synthesis of new contractile proteins and the assembly of new sarcomeres. The pattern in which these sarcomeres are laid down determines whether the myocytes elongate or increase their diameter [15]. Angiotensin II production is enhanced locally in the noninfarcted myocardium, and this enhanced production is a likely stimulus for hypertrophy [16]. Initially, this hypertrophy is an adaptive response to preserve stroke volume [13]; however, the end result is further deterioration in cardiac performance and increased neurohormonal activation [17]. Mechanical deformation of the myocyte membrane, as seen with increased left ventricular filling pressure, is associated with protein synthesis and enlargement of the cardiac myocytes [18,19]. Neuro-
Fig.1. Cardiac remodeling over time in infarct and noninfarct regions after transmural infarction. (From Rumberger JA. Ventricular dilatation and remodeling after myocardial infarction. Mayo Clin Proc 1994;69:664 – 74, with permission.)
S. Paul / Crit Care Nurs Clin N Am 15 (2003) 407–411
hormonal factors such as angiotensin II, norepinephrine, and endothelin are associated with an increase in cardiac cell size and hypertrophy [20]. The presence of angiotensin II, tumor necrosis factor-a (TNF-a), endothelin-1, and catecholamines seems also to be associated with an increase in MMPs [21]. Increased aldosterone production in response to increased levels of angiotensin II stimulates collagen synthesis by myocardial fibroblasts and contributes to fibrosis of the infarcted and noninfarcted regions of the ventricle [22]. Cytokines are peptides, distinct from neurotransmitters or neurohormones, that are released locally in response to injury, promoting inflammation. Cytokines such as TNF-a are released from the heart or from inflammatory cells that have migrated into the infarct zone and are presumed to contribute to hypertrophy and apoptosis. Circulating levels of TNF-a and other inflammatory cytokines are elevated in heart failure patients and can regulate growth and gene expression in cardiac myocytes and other cells in the myocardium [23,24]. Apoptosis is a term used to describe a genetically programmed, energy-requiring process of cell death, distinct from necrosis, in which cells involute, condense, and shrink. The cells fragment into smaller apoptotic bodies that are efficiently removed by neighboring cells or phagocytes. Rapid removal of the contained apoptotic cells prevents the influx of inflammatory cells that typically cause significant collateral damage to surrounding normal tissues. This process is likened to dead leaves falling off a tree and is a defense mechanism to rid an organ of damaged or infected cells without the inflammatory process. Endothelin-1 is a peptide that plays a minor role in normal cardiovascular function but is elevated in heart failure patients and assumes a major role in the regulation of hemodynamics, vascular and myocardial function, and remodeling. It has potent vasoconstrictor properties, stimulates neurohormonal activation, and contributes to remodeling through pathologic hypertrophy and myocardial fibrosis. Additionally, endothelin can be proinflammatory and proarrhythmic. As remodeling progresses, the extracellular matrix forms a collagen scar at the infarct site to stabilize the wall stress and prevent further deformation [5,25]. Within 1 month after an MI, the necrotic myocytes in the infarct zone are entirely replaced by fibrous tissue [9]. Collagen accumulation occurs in noninfarcted myocardium as well. This matrix accumulates in the interstitial spaces, and diastolic function is impaired as the ventricular chamber becomes stiff. As the heart undergoes remodeling, it becomes
409
less elliptical and more spherical in shape [26]. Eventually, systolic performance becomes compromised, and clinical heart failure is evident [20]. The greater the extent of remodeling, the poorer the patient’s prognosis [17].
Factors influencing cardiac remodeling Hypertension Endogenous vasoconstrictors are normally offset by endogenous vasodilators. In heart failure, however, vasoconstrictors seem to predominate over vasodilators, and the forces become unbalanced. Vasoconstriction is enhanced by amplification of neurohormones such as angiotensin II, aldosterone, and endothelin-1 during the remodeling process. Elevation of blood pressure can increase left ventricular pressure and exacerbate infarct expansion and thinning. Patency of infarct-related artery Researchers have found that patients with collateral circulation and those with subtotal occlusion do not undergo as much left ventricular dilatation as those with similar-sized infarctions caused by complete coronary occlusion. The degree of coronary perfusion was found to be a more important predictor of volume change within the ventricle than the actual size of the infarct [27]. Reperfusion may salvage endocardial tissue and restore stunned myocardium in the infarct border zone. Location and size of infarct Infarct size and location determine the likelihood of late remodeling ( > 72 hours after the infarct). Additionally, infarct expansion occurs more often with left anterior descending coronary artery occlusion than with right coronary artery occlusion and is associated with large transmural infarcts [28]. Neurohormone activation Neurohormonal activation mediates compensatory changes in the heart in response to decreased cardiac output with heart failure. Angiotensin II, norepinephrine, and vasopressin exert effects on the myocytes to potentiate the remodeling process. These neurohormones, along with cytokines and endothelin, promote the progression of heart failure and the remodeling process.
410
S. Paul / Crit Care Nurs Clin N Am 15 (2003) 407–411
Summary Ventricular remodeling is an extremely complicated process that is not well understood. There seem to be multiple feedback loops that respond to mechanical events as well as to neurohormonal stimulation, cytokine release, and other, yet unidentified, agents. The progression of ventricular remodeling after the index event includes Myocyte slippage and thinning of infarct area, chamber dilatation Fibrosis and scar formation Collagen strut dissolution and excessive accumulation of interstitial matrix Increased wall stress Myocyte hypertrophy Neurohormonal activation Cytokine release Ongoing myocyte hypertrophy Cell apoptosis and necrosis Continued deterioration of cardiac function It is impossible to place the sequence of events in order, because the multiple feedback systems create a complex interactive process. A basic awareness of the pathophysiology of ventricular remodeling can aid in understanding current and future treatments for heart failure. It is clear that therapeutic interventions solely aimed at improving cardiac pump function do not slow the progression of heart failure or reduce mortality [29 – 31]. Drugs that block the neuroendocrine contribution to the remodeling process have been shown to have a greater impact [32]. Current therapies with angiotensin-converting enzyme inhibition, b blockade, and aldosterone antagonism are associated with significant reductions in morbidity and mortality in heart failure. Other therapeutic strategies suggested by knowledge of remodeling mechanisms, such as drugs to block cytokines, endothelins, and MMPs, may offer further benefit to patients with heart failure in the future.
References [1] Vasam R, Larson M, Benjamin E, et al. Left ventricular dilatation and the risk of congestive heart failure in people without myocardial infarction. N Engl J Med 1997;336:1350 – 5. [2] Thomas K, Redfield M. Asymptomatic left ventricular dysfunction. Heart Fail Rev 1997;2:11 – 22. [3] Kannel W, Belanger A. Epidemiology of heart failure. Am Heart J 1991;121:951 – 7.
[4] Smith W. Epidemiology of congestive heart failure. Am J Cardiol 1985;55:3A – 8A. [5] Sutton MSJ, Sharpe N. Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation 2000;101:2981 – 8. [6] Giannuzzi P, Temporelli P, Bosimini E, et al. Heterogeneity of left ventricular remodeling after acute myocardial infarction. Am Heart J 2001;141:131. [7] Korup E, Dalsgaard D, Nyvad O, et al. Comparisons of degrees of left ventricular dilation within 3 hours and up to 6 days after onset of first acute myocardial infarction. Am J Cardiol 1997;80:449. [8] Erlebacher J, Weiss J, Weisfeldt M, et al. Early dilation of the infarcted segment in acute transmural myocardial infarction: role of infarct expansion in acute left ventricular enlargement. J Am Coll Cardiol 1984; 4:201 – 8. [9] Cleutjens J, Kandala J, Guarda E, et al. Regulation of collagen degradation in the rat myocardium after infarction. J Mol Cell Cardiol 1995;27:1281 – 92. [10] Spinale F, Coker M, Thomas C, et al. Time-dependent changes in matrix metalloproteinase activity and expression during the progression of congestive heart failure. Circ Res 1998;82:482 – 95. [11] Dollery C, McEwan J, Henney A. Matrix metalloproteinases and cardiovascular disease. Circ Res 1995; 77:863 – 8. [12] Sadoshima J, Jahn L, Takahashi T, et al. Molecular characterization of the stretch-induced adaptation of cultured cardiac cells: an in vitro model of load-induced cardiac hypertrophy. J Biol Chem 1992;267:10551 – 60. [13] Lew W, Chen Z, Guth B, et al. Mechanisms of augmented segment shortening in nonischemic areas during acute ischemia of the canine left ventricle. Circ Res 1985;56:351 – 8. [14] Anversa P, Olivetti G, Capasso J. Cellular basis of ventricular remodeling after myocardial infarction. Am J Cardiol 1991;68:7D – 16D. [15] Francis G, McDonald K. Left ventricular hypertrophy: an initial response to myocardial injury. Am J Cardiol 1992;69:3G – 6G. [16] Lindpaintner K, Lu W, Neidermajer N, et al. Selective activation of cardiac angiotensinogen gene expression in post-infarction ventricular remodeling in the rat. J Mol Cell Cardiol 1993;25:133 – 43. [17] Cohn J, Ferrari R, Sharpe N. Cardiac remodeling – concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. J Am Coll Cardiol 2000;35:569 – 82. [18] Schneider M, Roberts R, Parker T. Modulation of cardiac genes by mechanical stress: the oncogene signaling hypothesis. Mol Biol Med 1991;8:167 – 83. [19] Komuro I, Kaida T, Shibazake Y, et al. Stretching cardiac myocytes stimulates proto-oncogene expression. J Biol Chem 1990;265:3595 – 8. [20] Francis G. Pathophysiology of chronic heart failure. Am J Med 2001;110:37S – 46S. [21] Nagase H. Activation mechanisms of matrix metalloproteinases. Biol Chem 1997;378:151 – 60.
S. Paul / Crit Care Nurs Clin N Am 15 (2003) 407–411 [22] Brilla C, Zhou G, Matsubara L, et al. Collagen metabolism in cultured adult rat cardiac fibroblasts: response to angiotensin II and aldosterone. J Mol Cell Immunol 1994;26:809 – 20. [23] Torre-Amione G, Kapadia S, Benedict C, et al. Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol 1996;27:1206. [24] Levine B, Kalman J, Mayer L, et al. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 1990;323:236. [25] Cohen M, Yang X, Neumann T, et al. Favorable remodeling enhances recovery of regional myocardial function in the weeks after infarction in ischemically preconditioned hearts. Circulation 2000;102:579. [26] Mitchell G, Lamas G, Vaughan D, et al. Left ventricular remodeling in the year after first anterior myocardial infarction: a quantitative analysis of contractile segment lengths and ventricular shape. J Am Coll Cardiol 1992;19:1136.
411
[27] Jeremy R, Hackworthy R, Bautovich G, et al. Infarct artery perfusion and changes in left ventricular volume in the month after acute myocardial infarction. J Am Coll Cardiol 1987;9:989 – 95. [28] Pirolo J, Hutchins G, Moore G. Infarct expansion: pathologic analysis of 204 patients with a single myocardial infarct. J Am Coll Cardiol 1986;7:349 – 54. [29] Massie B, Fisher S, Deedwania P, et al. Effect of amiodarone on clinical status and left ventricular function in patients with congestive heart failure (CHF-STAT Investigation). Circulation 1996;93:2128 – 34. [30] The Digitalis Investigation Group. The effects of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997;336:525 – 33. [31] Packer M, Carver J, Rodeheffer R, et al. Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med 1991;325:1468 – 75. [32] Packer M. Evolution of the neurohormonal hypothesis to explain the progression of chronic heart failure. Eur Heart J 1995;16(Suppl F):4 – 6.