Alterations in Ventricular Structure: Role of Left Ventricular Remodeling and Reverse Remodeling in Heart Failure

One of the major conceptual advances in the field of heart failure (HF) has been the recognition that HF progresses because of the structural changes that occur in the heart in response to hemodynamic, neurohormonal, epigenetic and genetic factors. Although the complex changes that occur in the heart during left ventricular (LV) remodeling have traditionally been described in anatomic terms, the process of LV remodeling arises secondary to changes in biology of the cardiac myocyte, histological changes resulting from changes in the volume of myocyte and nonmyocyte components of the myocardium, as well as macroscopic changes in the geometry and architecture of the LV chamber ( Table 12.1 ). Clinical studies have shown that resolution of the cardiac injury that led to myocardial dysfunction and/or the implementation of medical and device therapies that reduce HF morbidity and mortality, results in a reversal of LV remodeling, which is characterized anatomically by a return in LV volume and mass toward normal values, as well as a shift in the LV end-diastolic pressure-volume relationship (EDPVR) to the left. These salutary changes represent the summation of a series of integrated biologic changes in cardiac myocyte size and function, as well as modifications in LV structure and organization. For want of better terminology, these changes have been referred to collectively as reverse remodeling . A small subset of patients experience sufficient reverse remodeling to regain a normal ejection fraction (EF) in a process that has been referred to as myocardial recovery. The rate of normalization in left ventricular ejection fraction (LVEF) depends on the underlying etiology of the cardiomyopathy. Moreover, there is growing body of evidence that suggests that, even among patients who experience a complete normalization in LVEF, there is tremendous heterogeneity and that a significant proportion will have recurrent LV dysfunction and recurrent HF events. The importance of understanding the biology of LV remodeling, reverse LV remodeling, and the subtleties of myocardial recovery is that it may lead to the identification of novel therapeutic targets for treating/reversing HF. In the chapter that follows, we will discuss the changes that occur during the process of LV dilation in HF with a reduced EF. The remodeling that occurs in HF with a preserved EF is discussed in Chapter 11 .

Left Ventricular Remodeling

The term left ventricular (LV) remodeling describes the changes in mass, volume, shape, and composition observed in the LV in response to mechanical stimulation and systemic neurohormonal activation. Conceptually, these changes can be envisioned as occurring within the cardiac myocyte, in the histological structure of the myocardium, and within the LV chamber.

Alterations in the Biology of the Cardiac Myocyte

The changes that occur in the biology of the failing cardiac myocyte include (1) cell hypertrophy ( see Chapter 2 ); (2) reactivation of fetal genes; (3) β-adrenergic desensitization ( see Chapter 6 ); (4) loss of myofibrils and progressive disarray of the cytoskeleton; (5) changes in excitation-contraction coupling leading to alterations in the contractile properties of the myocyte ( see Chapter 2 ); and (6) modifications of myocyte metabolism ( see Chapter 17 ). Collectively these changes lead to decreased shortening and delayed relaxation of the failing cardiac myocyte.

Two basic patterns of cardiac hypertrophy occur in response to hemodynamic overload ( Fig. 12.1 ). In pressure overload hypertrophy (e.g., with aortic stenosis or hypertension), the increase in systolic wall leads to the addition of sarcomeres in parallel, an increase in myocyte cross-sectional area, and increased LV wall thickening. This pattern of remodeling has been referred to as concentric hypertrophy (see Fig. 12.1A ) and has been linked with alterations in calcium/calmodulin-dependent protein kinase II-dependent signaling. In contrast, in volume overload hypertrophy (e.g., with aortic and mitral regurgitation), increased diastolic wall stress leads to an increase in myocyte length with the addition of sarcomeres in series, thereby engendering increased LV dilation. This pattern of remodeling has been referred to as eccentric hypertrophy (so named because of the position of the heart in the chest) or a dilated phenotype (see Fig. 12.1A ) and has been linked with Akt activation. Patients with HF classically present with a dilated LV with or without LV thinning. The myocytes from these failing ventricles have an elongated appearance that is characteristic of myocytes obtained from hearts subjected to chronic volume overload. Cardiac myocyte hypertrophy leads to reactivation of portfolios of genes that are normally not expressed postnatally. The reactivation of these fetal genes, the so-called fetal gene program, is also accompanied by decreased expression of a number of genes that are normally expressed in the adult heart including the gene for the β1 adrenergic receptor with resulting β-adrenergic desensitization ( see Chapter 6 ). As will be discussed below, activation of the fetal gene program may contribute to the contractile dysfunction that develops in the failing myocyte in many other ways. The stimuli for the genetic reprogramming of the myocyte include mechanical stretch/strain of the myocyte, neurohormones (e.g., NE, angiotensin II), inflammatory cytokines (e.g., tumor necrosis factor [TNF], interleukin-6 [IL-6]), other peptides and growth factors (e.g., ET), and reactive oxygen species (e.g., superoxide, NO). These stimuli occur both locally within the myocardium, where they exert autocrine/paracrine effects, as well as systemically where they exert endocrine effects.

The early stage of cardiac myocyte hypertrophy is characterized morphologically by increases in the number of myofibrils and mitochondria, as well as enlargement of mitochondria and nuclei ( Fig. 12.2 ). At this stage the cardiac myocytes are larger than normal and have preserved cellular organization. As hypertrophy continues, there is an increase in the number of mitochondria, as well as the addition of new contractile elements in localized areas of the cell. Cells subjected to long-standing hypertrophy show more obvious disruptions in cellular organization, such as markedly enlarged nuclei with highly lobulated membranes, accompanied by the displacement of adjacent myofibrils with loss of the normal registration of the Z bands. The late stage of hypertrophy is characterized by loss of contractile elements (myocytolysis) with marked disruption of Z bands, severe disruption of the normal parallel arrangement of the sarcomeres, accompanied by dilation and increased tortuosity of T tubules.

Failing human cardiac myocytes also undergo a number of other important changes expected to lead to a progressive loss of contractile function, including decreased α-myosin heavy chain gene expression with a concomitant increase in β-myosin heavy chain expression. The cytoskeleton of the myocyte consists of actin, the intermediate filament desmin, the sarcomeric protein titin, and α- and β-tubulin that form microtubules by polymerization. Vinculin, talin, dystrophin, and spectrin represent a separate group of membrane-associated proteins. The failing myocyte shows alterations in cytoskeletal proteins, and in numerous experimental models cytoskeletal and/or membrane-associated proteins have been implicated in the pathogenesis of HF. This is accompanied by alterations in excitation-contraction coupling that have been closely linked to myocardial contractile dysfunction ( see Chapter 2 ). These changes include modification in the abundance of critical Ca ²⁺ regulatory proteins including sarcoplasmic endoreticular Ca ²⁺ ATPase (SERCA), ryanodine receptor (RyR), L-type calcium channel (LTCC), and sarcolemmal Na ⁺ /Ca ²⁺ exchanger (NCX). Furthermore, several lines of evidence suggest that the failing myocyte experiences metabolic changes, which leads to impaired efficiency of myocardial energetics ( see Chapter 17 ). When the contractile performance of isolated failing human myocytes was examined under very simple experimental conditions, investigators found that there is an approximately 50% decrease in cell shortening in failing human cardiac myocytes when compared with nonfailing human myocytes.

Alterations in the Myocardium

The alterations that occur in failing myocardium may be categorized broadly into those that occur within the cardiac myocyte compartment, those that occur in the volume and composition of the extracellular matrix (ECM), as well as changes in the myocardial microvasculature. With respect to the changes that occur in the cardiac myocyte component of the myocardium, there is increasing evidence to suggest that progressive myocyte loss may contribute to the development of LV dysfunction and LV remodeling. Necrotic and apoptotic cell death are discussed in Chapter 2 . Whereas the distinction between necrosis and apoptosis is obvious in certain circumstances, the dividing line between these two conditions is often less clear in the failing heart. And indeed, similar mechanisms can operate in both types of cell death. Thus instead of the existence of distinct types of cell death in HF, there is likely a continuum of cell death responses that contribute to progressive myocyte loss and disease progression.

Changes within the ECM constitute the second important myocardial adaptation that occurs during cardiac remodeling and include changes in overall collagen content, changes in the relative contents of different collagen subtypes, changes in collagen cross-linking, and modifications of the connections between cells and the ECM via integrins. Studies in failing human myocardium have shown that there is a quantitative increase in collagen I, III, VI, and IV; fibronectin; laminin; and vimentin, and that the ratio of type I collagen to type III collagen is decreased in patients with ischemic cardiomyopathy. Moreover, clinical studies suggest that there is a progressive loss of cross-linking of collagen in the failing heart, as well as loss of connectivity of the collagen network with individual myocytes, which would be expected to result in profound alterations in LV structure and function. Further, loss of cross-linking of the fibrillar collagen has been associated with progressive LV dilation following myocardial injury. The accumulation of collagen can occur on a “reactive” basis around intramural coronary arteries and arterioles (perivascular fibrosis) or in the interstitial space (interstitial fibrosis), and does not require myocyte cell death ( Fig. 12.3 ). Alternatively, collagen accumulation can occur as a result of microscopic scarring (replacement fibrosis) that develops in response to cardiac myocyte cell necrosis. This scarring or “replacement fibrosis” is an adaptation to the loss of parenchyma and is therefore critical to preserve the structural integrity of the heart. The increased fibrous tissue would be expected to lead to increased myocardial stiffness, which would presumably result in decreased myocardial shortening for a given degree of afterload. In addition, myocardial fibrosis may provide the structural substrate for atrial and ventricular arrhythmias, thus potentially contributing to sudden death. Although the full complement of molecules responsible for fibroblast activation is not known, many of the classical neurohormones (e.g., angiotensin II, aldosterone) and cytokines (ET, transforming growth factor-β [TGF-β], cardiotrophin-1) that are expressed in HF are sufficient to provoke fibroblast activation. And indeed, the use of angiotensin-converting enzyme (ACE) inhibitors, β-blockers, and aldosterone receptor antagonists has been associated with a decrease in myocardial fibrosis in experimental HF models.

Although the fibrillar collagen matrix was initially considered to form a relatively static complex, it is now recognized that these structural proteins can undergo rapid turnover. As discussed in Chapter 4 , one of the more exciting developments with respect to understanding the pathogenesis of cardiac remodeling has been the discovery that a family of collagenolytic enzymes, collectively referred to as matrix metalloproteinases (MMPs), are activated within the failing myocardium. Conceptually, disruption of the ECM would be expected to lead to LV dilation and wall thinning as a result of mural realignment (slippage) of myocyte bundles and/or individual myocytes within the LV wall, as well as LV dysfunction as a result of dyssynchronous contraction of the LV. Although the precise biochemical triggers that are responsible for activation of MMPs are not known, it bears emphasis that TNF, as well as other cytokines and peptide growth factors that are expressed within the failing myocardium, is capable of activating MMPs. However, the biology of matrix remodeling in HF is likely to be much more complex than the simple presence or absence of MMP activation. In fact, degradation of the matrix is also controlled by glycoproteins termed tissue inhibitors of matrix metalloproteinases (TIMPs), which are capable of regulating the activation of MMPs by binding to and preventing these enzymes from degrading the collagen matrix of the heart. The TIMP family presently consists of four distinct members, known as TIMP-1, -2, -3, and -4, each of which is constitutively expressed in the heart by fibroblasts, as well as myocytes. TIMPs-1, -2, -3, and -4 are secreted proteins that act as the natural inhibitors of active forms of all MMPs, although the efficiency of MMP inhibition varies among the different members. The existing literature suggests that MMP activation can lead to progressive LV dilation, whereas TIMP expression favors progressive myocardial fibrosis ( see Chapter 4 ).

The histologic modifications of the failing myocardium are not limited to the ECM but also involve significant changes in the relationship between cardiac myocytes and their blood supply. In fact, although cardiac growth and angiogenesis are tightly coordinated during development and physiologic cardiac growth, following hemodynamic overload and/or cardiac injury it is easy to observe a mismatch between cardiac myocyte growth and blood supply that may lead to contractile dysfunction and cell death. This has been especially well documented in patients with dilated cardiomyopathy that have a reduced myocardial capillary density. Thus impaired capillary growth may contribute to the development and/or progression of HF.

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