Pathophysiology of heart failure with reduced ejection fraction: Hemodynamic alterations and remodeling

INTRODUCTION — Heart failure (HF) is a clinical syndrome caused by impairment of ventricular filling or ejection of blood [1], which results in the inability of the heart to provide adequate perfusion to the tissues while maintaining normal cardiac filling pressures. HF is associated with a variety of interrelated structural, functional, and neurohumoral alterations with beneficial as well as maladaptive effects.

This topic will discuss the hemodynamic and remodeling aspects of the pathophysiology of HF, particularly HF with reduced ejection fraction (HFrEF; left ventricular ejection fraction [LVEF] ≤40 percent) and HF with mid-range ejection fraction (HFmrEF; LVEF 41 to 49 percent). The pathophysiology of neurohormonal alternations in HF, the diagnosis and management of HFrEF and HFmrEF, and the pathogenesis of HF with preserved ejection fraction (HFpEF, LVEF ≥50 percent) are discussed separately. (See "Pathophysiology of heart failure: Neurohumoral adaptations" and "Heart failure: Clinical manifestations and diagnosis in adults" and "Determining the etiology and severity of heart failure or cardiomyopathy" and "Treatment and prognosis of heart failure with mildly reduced ejection fraction" and "Pathophysiology of heart failure with preserved ejection fraction" and "Overview of the management of heart failure with reduced ejection fraction in adults".)

LVEF CATEGORIES AND LIMITATIONS — As discussed below, the two major types of ventricular dysfunction that lead to HF are systolic dysfunction (impaired cardiac contractile function) and diastolic dysfunction (impaired cardiac filling), although these mechanisms are often concurrent (see 'Pressure-volume relationships in HF' below). For clinical purposes, HF due to LV dysfunction is categorized according to LVEF. Nearly one-half of patients with HF have HFrEF (LVEF ≤40 percent), and nearly one-half have HFpEF (LVEF ≥50 percent) [2]. The remaining 10 to 24 percent of patients with HF have HFmrEF (LVEF 41 to 49 percent) [3-14].

However, categorization of LV function and HF by LVEF is not based upon etiology or pathophysiology, but rather by clinical convention given the prognostic value of LVEF, inclusion of LVEF thresholds as criteria in clinical HF trials, and the widespread availability of methods to measure LVEF (particularly echocardiography). LVEF is not a robust measure of contractility [15], commonly changes over time, and is subject to substantial variability among and within modalities. (See 'Contractility' below and "Tests to evaluate left ventricular systolic function", section on 'Left ventricular ejection fraction'.)

Patients with the same LVEF may have differing underlying pathophysiology and prognosis. Despite these limitations, depressed LVEF is an adverse prognostic indicator in HF patients, with increasing morbidity and mortality as LVEF falls below 40 to 50 percent. (See "Predictors of survival in heart failure with reduced ejection fraction", section on 'Left ventricular ejection fraction' and "Prognosis of heart failure", section on 'Factors affecting mortality rates'.)

NORMAL LV PRESSURE-VOLUME RELATIONSHIP — As a pump, the ventricle generates pressure and displaces a volume of blood. The three major determinants of LV performance (reflected as stroke volume) are the preload (reflected by venous return and end-diastolic volume), myocardial contractility (the force generated at any given end-diastolic volume), and the afterload (aortic impedance and wall stress) [16]. The relationship between LV pressure generation and ejection can be expressed as a plot of LV pressure versus LV volume (figure 1).

Preload — Preload is defined as the particular stretch or length of LV myocardial fibers at end-diastole, which is determined by the resting force, myocardial compliance, and the degree of filling from the left atrium. Landmark studies by Frank and Starling established the relationship between ventricular end-diastolic volume (which is a measure of preload) and ventricular performance (stroke volume). Increasing sarcomere length up to a point increases the degree of overlap between actin and myosin filaments for force-generating cross-bridges, thereby enabling increased tension development (figure 2) [17]. Thus, there is an augmentation of developed force as end-diastolic volume and fiber length increase up to a point. The LV normally functions on the ascending limb of this force-length relationship.

Contractility — Myocardial contractility is defined by the force generated at any given preload. Thus, the stroke volume at any given fiber length is a function of contractility, as variations in contractility create nonparallel shifts in the developed force-length relation. The tension in each myocardial cell is a function of the amount of calcium bound to a regulatory site on the troponin complex of the myofilaments. The amount of calcium available is in turn a function of intracellular calcium delivery.

Although LVEF is often assumed to be a measure of cardiac function, it is important to recognize the profound effect of structural changes. LV remodeling results in myocyte lengthening that increases chamber volume and results in an obligatory reduction in LVEF not necessarily caused by impaired contractile function. (See 'Remodeling' below.)

Afterload — A third element determining ventricular performance is the afterload, the impedance during ejection. The afterload on the shortening fibers is defined as the force per unit area acting in the direction in which these fibers are arranged in the ventricular wall. This constitutes the wall stress and can be estimated by applying Laplace's Law [18]. Changes in ventricular volume and wall thickness, as well as aortic pressure or aortic impedance, determine the afterload. As an example, elevations in systolic pressure reduce the ventricular stroke volume at any given diastolic volume. In the normal heart, stroke volume is only minimally altered by changes in afterload.

The relationship among preload, afterload, and contractility provides a type of feedback control of myocardial function. A primary increment in stroke volume, for example, leads to an increase in aortic impedance. As a result of this rise in afterload, subsequent contractions have an attenuated stroke volume. If, on the other hand, an increment in aortic impedance is the initial event, the accompanying reduction in stroke volume should lead to a greater end-ejection and end-diastolic chamber volume. The ensuing prolongation of fiber length should restore stroke volume to the baseline level.

PRESSURE-VOLUME RELATIONSHIPS IN HF — The two major types of ventricular dysfunction that lead to HF are systolic dysfunction (impaired cardiac contractile function) and diastolic dysfunction (impaired cardiac filling), although these mechanisms are interrelated and often concurrent. Systolic and diastolic dysfunction of the LV can be understood by analysis of the relationships between LV-developed pressure and volume [19-21].

LV systolic dysfunction refers to decreases in the length-tension relationship and in myocardial contractility. Systolic dysfunction causes a shift in the Frank-Starling curve downward and to the right (figure 3), a downward shift in the end-systolic pressure-volume relationship (ESPVR), and a decrease in the slope of the ESPVR relationship over a range of pressures [22]. These changes are associated with a reduction in the stroke volume for a given amount of preload.

Drug therapy can alter the developed force-length relationship. For example, the administration of dobutamine stimulates cardiac beta-adrenergic receptors, which increase myocardial cell cyclic adenosine monophosphate levels, thereby raising the intracellular calcium concentration and contractility. As a result, the ventricle is able to develop a greater force from any given fiber length. Administration of a beta blocker, on the other hand, attenuates the slope of the force-length relationship.

Hemodynamic changes associated with systolic dysfunction trigger neurohumoral activation as well as cardiac remodeling. The fall in cardiac output leads to increased sympathetic activity, which helps to restore cardiac output by increasing both contractility and heart rate. The fall in cardiac output also promotes renal salt and water retention, leading to expansion of the blood volume, thereby raising end-diastolic pressure and volume, which, via the Frank-Starling relationship, enhance ventricular performance and tend to restore the stroke volume (figure 3). LV hypertrophy is also part of the adaptive response to systolic dysfunction, since it unloads individual muscle fibers and thereby decreases wall stress and afterload. (See 'Remodeling' below and "Pathophysiology of heart failure: Neurohumoral adaptations".)

As systolic HF progresses, the progressive decline in the maximal cardiac output generated for any given cardiac filling pressure can be represented as a series of Frank-Starling curves (figure 3). Flattening of the Frank-Starling curve in advanced disease means that augmentation in venous return and LV end-diastolic pressure (LVEDP) now fails to increase stroke volume. The plateau in the Frank-Starling curve represents a reduction in the heart's systolic reserve. As a result, the ability of positive inotropic agents to shift this relationship to the left and permit greater shortening becomes impaired. In terms of the pressure-volume plot, the systolic pressure-volume point is "right-shifted" in systolic HF. In addition, the ESPVR slope is decreased, which represents decreased contractility. The diastolic pressure-volume curve is initially normal in systolic HF but shifts to the right as the heart dilates. This rightward shift is due to an increase in LV volume caused by cardiac dilation (figure 4).

Two factors may contribute to a plateau in the pressure-volume curve:

●The heart may simply have reached its maximum capacity to increase contractility in response to increasing stretch. In vitro studies suggest that this abnormality may result from decreased calcium affinity for troponin C, and from decreased calcium availability within the myocardial cells [23]. These abnormalities may result in part from lengthening of the sarcomeres to a point that exceeds the optimal degree of overlap of thick and thin myofilaments, thereby preventing developed force from increasing in response to increasing load.

●The Frank-Starling relationship actually applies to LV end-diastolic volume, since it is the stretching of cardiac muscle that is responsible for the enhanced contractility. The more easily measured LVEDP is used clinically, since in relatively normal hearts, pressure and volume vary in parallel. However, cardiac compliance may be reduced with heart disease. As a result, a small increase in volume may produce a large elevation in LVEDP, but no substantial stretching of the cardiac muscle and therefore little change in cardiac output [24].

Decreased compliance due to hypertrophy and fibrosis may eventually produce disturbed diastolic function in many patients with advanced HF [21]. In this setting, there is also an upward shift in the end-diastolic pressure-volume relationship, as a higher pressure is required to achieve the same volume. In addition, disturbances in calcium handling by the sarcoplasmic reticulum leading to impaired reuptake of calcium during diastole may contribute to both systolic dysfunction due to diminished calcium stores available for release with depolarization and diastolic dysfunction (slowed relaxation) due to impaired calcium reuptake during diastole.

The failing heart is progressively more afterload-dependent, and small changes in afterload can produce large changes in stroke volume (figure 5). Reducing afterload in patients with HF via the administration of angiotensin converting enzyme inhibitors, angiotensin receptor blockers, or direct vasodilators (eg, hydralazine) has the dual advantage of increasing cardiac output and, over the long term, slowing the rate of pathological remodeling. (See "Overview of the management of heart failure with reduced ejection fraction in adults".)

REMODELING — Remodeling is defined as alteration in the structure (ie, dimensions, mass, and shape) of the heart (also called cardiac or ventricular remodeling) in response to hemodynamic load and/or cardiac injury, in association with neurohormonal activation and other factors. The process of cardiac remodeling includes structural, functional, cellular, and molecular changes involving cardiac myocytes and the interstitial collagen matrix.

Remodeling may be categorized as physiologic (adaptive) or pathologic (maladaptive) [25,26]:

●Physiologic remodeling is a compensatory change in the dimensions and function of the heart in response to physiologic stimuli, such as exercise and pregnancy. This type of remodeling is seen in athletes and has been called "athlete's heart." (See "Definition and classification of the cardiomyopathies", section on 'Athlete's heart'.)

●Pathologic remodeling may occur with pressure overload (eg, aortic stenosis, hypertension), volume overload (eg, valvular regurgitation), or following cardiac injury and may be localized (eg, myocardial infarction [MI]) or diffuse (eg, myocarditis or idiopathic dilated cardiomyopathy). In each of these settings, remodeling may transition from an apparently compensatory process to a maladaptive one [27]. (See 'Adaptive versus maladaptive processes' below.)

Structural and functional changes — The remodeling process generally includes increases in myocardial mass, and the myocyte is the major cell involved in the remodeling process. Other components include the interstitium, fibroblasts, collagen, and coronary vasculature. Myocardial hypertrophy is most properly defined as increased cardiomyocyte size with or without an increase in overall myocardial mass; however, the term "hypertrophy" is used clinically to denote increased myocardial mass and/or wall thickness.

Three general morphologic patterns of remodeling have been described (figure 6) [27,28]:

●Pressure overload leads to concentric LV remodeling with or without an overall increase in myocardial mass [29]. Concentric remodeling is characterized by increased relative wall thickness (ventricular wall thickness as compared with cavity size). With concentric hypertrophy, sarcomeres are added in parallel, and individual cardiomyocytes grow thicker.

●Volume overload or isotonic exercise leads to eccentric LV hypertrophy [29]. Eccentric LV hypertrophy is characterized by increased cardiac mass and chamber volume. Relative wall thickness may be normal, increased, or decreased. With eccentric hypertrophy, sarcomeres are added in series, and individual cardiomyocytes grow longer.

●Following an MI, stretched, infarcted tissue increases LV volume, leading to combined volume and pressure load on noninfarcted zones and mixed concentric/eccentric hypertrophy. LV remodeling typically begins within the first few hours after the infarct, and progresses over time [30-33]. The initial remodeling phase after an MI results in repair of the necrotic area and scar formation that may, to some extent, be considered beneficial, since there is an improvement in or maintenance of LV function and cardiac output [34,35]. The entire heart may be involved, as disproportionate thinning and dilation in the infarct region (ie, infarct expansion) are accompanied by a distortion in shape of the entire heart with volume-overload hypertrophy of noninfarcted myocardium [31,36]. As the heart undergoes remodeling, it becomes less elliptical and more spherical (figure 7) [37,38]. There are also changes in ventricular mass, composition, and volume, all of which may adversely affect cardiac function [36,39-42]. This cellular rearrangement of the ventricular wall is associated with a significant increase in LV volume. Some studies have shown that this volume increase is not a prerequisite to maintaining LV function.

Progressive remodeling is common after an initial, moderately large anterior wall Q-wave infarction, but is unusual after an initial small inferior wall infarction [40]. Patients with no or limited dilation at four weeks tend to remain stable, while those with progressive dilation over this period tend to deteriorate over time with loss of function in initially normally contracting myocardium (ie, pathologic remodeling) [36,39,40]. These changes are important predictors of mortality [43]. However, mechanisms other than remodeling can influence the course of heart disease, and disease progression can occur in the absence of remodeling.

The importance of remodeling as an independent risk factor has been difficult to ascertain, since factors leading to remodeling as well as the remodeling itself may be major determinants of HF prognosis. Consistent with the hypothesis that remodeling is pathogenically important in HF is the observation that angiotensin converting enzyme (ACE) inhibitors and some beta blockers, which improve survival in patients with HF, can slow and in some cases even reverse certain parameters of cardiac remodeling [44-48]. In addition, reversal of remodeling with mechanical circulatory support in combination with medical therapy is associated with improvement in LV systolic function in patients with advanced HF [49-52]. (See "Treatment of advanced heart failure with a durable mechanical circulatory support device" and "Overview of the management of heart failure with reduced ejection fraction in adults".)

Adaptive versus maladaptive processes — As noted above, cardiac remodeling is both an adaptive and a maladaptive process. The adaptive component enables the heart to maintain function in response to pressure or volume overload in the acute phase of cardiac injury [53].

By comparison, progressive remodeling is deleterious and associated with a poor prognosis [39,43]. There are no data to indicate when the transition from possibly adaptive to maladaptive remodeling occurs, or how this might be identified in patients. The occurrence of such a transition and its time course may be expected to vary greatly. However, once established beyond a certain phase, it is likely that remodeling actually contributes to HF progression. In addition, it has been suggested that remodeling and the myocardial changes that accompany it contribute to the pathogenesis of ventricular arrhythmias. (See "Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features".)

Cellular and molecular changes — Remodeling is associated with a number of cellular changes that underlie structural remodeling, including myocyte hypertrophy, loss of myocytes due to apoptosis [54-56] or necrosis [57], and fibroblast proliferation [58] and fibrosis [59,60]. These structural changes are a reflection of molecular events, which include alterations in the abundance, function, and isoforms of proteins involved in the regulation of cellular growth, survival, excitation-contraction coupling, and energetics. Many forms of myocardial remodeling are associated with increased expression of genes that are typical of the fetal heart (eg, B-type natriuretic peptide, myosin heavy chain). In addition, posttranslational changes may affect protein function and abundance that alter many aspects of cellular homeostasis.

Mechanical strain on the myocyte and circulating neurohormones plays an important role in triggering the signaling pathways that mediate hypertrophy, apoptosis, excitation-contraction coupling, and energetics [34,61-63]. (See 'Neurohormonal activation' below.)

Cardiac myocytes — Myocytes and other cardiac cell types are thought to be fundamentally involved in the remodeling process. After an insult of sufficient magnitude, myocyte numbers decrease and surviving myocytes become elongated or hypertrophied as part of a compensatory process to maintain stroke volume [41,42]; the thickness of the ventricular wall also may increase due to myocyte hypertrophy [36,41,42].

Altered loading conditions (eg, increased preload) stretch cell membranes and increase wall stress, which may play a role in inducing the expression of hypertrophy-associated genes. In cardiac myocytes, this may lead to the synthesis of new contractile proteins and the assembly of new sarcomeres. It is thought that the pattern in which these proteins are laid down determines whether the cardiac myocytes elongate or increase their diameter [64]. The increase in wall stress [41,62] may precipitate energy imbalance and ischemia, leading to a vicious cycle of increased wall stress and wall thickness, with further energy imbalance and ischemia.

Collagen synthesis and degradation — The myocardium consists of myocytes tethered and supported by a connective tissue network composed largely of fibrillar collagen. Collagen is synthesized by interstitial fibroblasts and degraded by locally produced enzymes called collagenases, such as matrix metalloproteinases (MMPs). The significance of collagen synthesis and degradation in cardiac remodeling and HF is supported by a variety of observations in humans and in animal models [59,60,65-73]. As in the cardiac myocyte, hemodynamic and neurohormonal factors act on the cardiac fibroblast and cause changes in collagen homeostasis, which contribute to abnormalities of the interstitium that affect the physical properties of the myocardium (eg, distensibility) and nutrient delivery to myocytes.

Apoptosis — It has been proposed that increased apoptosis with loss of myocytes contributes to progressive LV dysfunction in chronic HF [54]. The importance of this type of cell death in human cardiac remodeling is not firmly established. However, in myocardial samples from patients who underwent heart transplantation, apoptosis was increased more than 200-fold in the failing heart [56].

Likewise, increased apoptosis is associated with the maladaptive response to sustained pressure overload (increased afterload) in the rat [55]. Furthermore, in a mouse model of HF, specific inhibition of apoptosis was beneficial [74]. Additional evidence that apoptosis is involved in adverse remodeling and HF post-MI comes from mice in which the proapoptotic protein Bnip3 was ablated [75,76].

Functional remodeling — While cardiac remodeling is primarily described on a structural basis, "remodeling" also occurs at the molecular level, leading to alterations in the expression and function of proteins that have important nonstructural effects on properties such as contraction/relaxation, electrical activation, and metabolism. These molecular changes are commonly associated with structural remodeling but, not infrequently, occur in the absence of structural changes and, in either case, may have important consequences leading to alterations in substrate utilization, the genesis of arrhythmias, and abnormalities in contraction and relaxation.

Factors influencing cardiac remodeling — There are a number of factors that can influence remodeling, including LV hemodynamics, blood pressure, and neurohormonal activation. The time course and extent of remodeling are influenced by a variety of factors, including the severity of the underlying disease, secondary events (such as recurrent ischemia), and treatment [31,40,77]. Following an MI, the magnitude of remodeling changes is roughly related to infarct size [40,41].

Alterations in hemodynamic load — Alterations in hemodynamic load caused by myocardial injury influence the remodeling process. Early LV dilation in patients with anterior wall infarction may be progressive. On the other hand, compensatory ventricular hypertrophy appears to be a delayed and limited adaptation during the first year [40]. The net effect of progressive ventricular dilation with insufficient reactive ventricular hypertrophy is a considerable increase in global LV wall tension [40,78]. A number of mechanisms may be stimulated by increased wall stress which, in the absence of effective therapy, may lead to further dilation of the heart and progressive HF [42,79].

Blood pressure — Elevated blood pressure induces structural changes in the LV (eg, hypertrophy, interstitial changes), which may result in diastolic dysfunction that may progress to HF. The functional impact of pressure overload hypertrophy may be dependent on the nature of the remodeling process. When remodeling is eccentric (LV enlargement with normal relative wall thickness, but increased wall stress), a functional impairment leading to HF was observed [80]. In contrast, HF did not occur in animals with concentric remodeling (normal chamber size, increased relative wall thickness, and normal wall stress). There was no difference between the two groups in myocardial mass or contractile function.

Neurohormonal activation — Progressive HF is associated with neurohumoral activation that may be viewed initially as compensatory, but may be deleterious over the long term, in part by contributing to pathologic remodeling [81]. Types and effects of neurohormonal activation are discussed below. (See "Pathophysiology of heart failure: Neurohumoral adaptations", section on 'Neurohumoral adaptations'.)

The data are most compelling for activation of the renin-angiotensin-aldosterone system. Randomized trials have demonstrated that ACE inhibitors improve survival in HFrEF and can slow (and in some cases even reverse) certain parameters of cardiac remodeling. These findings indicate the importance of angiotensin II in pathologic remodeling [44-46]. Both systemic and locally generated angiotensin II may participate in this process.

Aldosterone, the secretion of which is enhanced by angiotensin II, also may participate in remodeling. The heart contains mineralocorticoid receptors and extracts aldosterone after an MI, contributing to post-infarction remodeling [82]. In addition, the secondary hyperaldosteronism commonly seen in HF may contribute to cardiac hypertrophy and fibrosis [83,84]. Part of the survival benefit associated with spironolactone or eplerenone, which compete for the mineralocorticoid receptor, may come from reduced fibrosis [85]. (See "Pharmacologic therapy of heart failure with reduced ejection fraction: Mechanisms of action", section on 'Mineralocorticoid receptor antagonists'.)

Other factors — Other factors can also contribute to remodeling, including cytokines (tumor necrosis factor-alpha [TNFa] and interleukins [IL]) [86], oxidative stress, MMPs, peripheral monocytosis [87], and endothelin. (See "Pathophysiology of heart failure: Neurohumoral adaptations", section on 'Endothelin'.)

●HF is often associated with increases in circulating proinflammatory cytokines (eg, TNFa, IL-6, IL-1-beta and IL-2, and their soluble receptor or receptor antagonists) that become more pronounced as myocardial function deteriorates [88-93]. Since inflammatory cytokines can exert deleterious effects on the heart, it is possible that they play a role in the pathophysiology of HF. Increased levels of proinflammatory cytokines and other inflammatory markers may identify patients at increased risk of developing HF in the future [94,95], and circulating concentrations of TNFa are increased in patients with HF in proportion to the severity of the disease [88,96]. Conversely, infusion of pathophysiologic concentrations of TNFa can produce changes similar to those seen in remodeling [97]. However, the clinical significance remains uncertain, as the use of inflammatory cytokine antagonists has not been beneficial in patients with HFrEF [95,98].

●Oxidative stress refers to an imbalance between production of oxygen free radicals and antioxidant defenses. There is increasing literature on its potential importance in progressive HF. Although antioxidant therapies have not been shown to be of value in patients with HF, markers of oxidative stress may be elevated in patients with HF. For example, myeloperoxidase (MPO) is a leukocyte-derived enzyme that can produce a cascade of reactive oxidative species, which may lead to lipid peroxidation, scavenging of nitric oxide, and nitric oxide synthase inhibition [99,100]. Plasma MPO levels are elevated in patients with chronic HFrEF [101], and elevated plasma MPO has been associated with an increased likelihood of more advanced HF, and may be predictive of a higher rate of adverse clinical outcomes [102].

●MMPs contribute to tissue remodeling in a number of disease states, such as an abdominal aortic aneurysm (see "Clinical features and diagnosis of abdominal aortic aneurysm"). MMPs have also been implicated in cardiac remodeling [103,104], and in animal models, remodeling can be attenuated by MMP inhibition [72,73,105].

●Peripheral monocytosis, which occurs two to three days after an acute MI, reflects monocyte and macrophage infiltration of the necrotic myocardium. A higher peak monocyte level is associated with a larger LV end-diastolic volume and lower LVEF. A peak monocyte count ≥900/microL independently predicts HF, LV aneurysm formation, and cardiac events [87].

SUMMARY

●Heart failure (HF) is associated with a variety of interrelated structural, functional, and neurohumoral alterations with beneficial as well as maladaptive effects. (See 'Introduction' above.)

●The three major determinants of the left ventricular (LV) performance (reflected as stroke volume) are the preload (venous return and end-diastolic volume), myocardial contractility (the force generated at any given end-diastolic volume), and the afterload (aortic impedance and wall stress). (See 'Normal LV pressure-volume relationship' above.)

●The relationship between LV pressure generation and ejection can be expressed as a plot of LV pressure versus LV volume (Frank-Starling curve) (figure 1). (See 'Normal LV pressure-volume relationship' above.)

•Systolic dysfunction causes a shift in the Frank-Starling curve downward and to the right (figure 3), a downward shift in the end-systolic pressure-volume relationship (ESPVR), and a decrease in the slope of the ESPVR relationship over a range of pressures. (See 'Pressure-volume relationships in HF' above.)

•Diastolic dysfunction causes an upward–shift in the end-diastolic pressure-volume relationship. (See 'Pressure-volume relationships in HF' above.)

●Remodeling is defined as an alteration in the structure of the heart in response to hemodynamic load and/or neurohormonal activation. Pathologic remodeling may occur with pressure overload (eg, aortic stenosis, hypertension), volume overload (eg, valvular regurgitation), or following cardiac injury (eg, myocardial infarction [MI]). In each of these settings, remodeling may transition from an apparently compensatory process to a maladaptive one. (See 'Remodeling' above and 'Adaptive versus maladaptive processes' above.)

•The three general patterns of remodeling are concentric LV remodeling (in response to pressure overload), eccentric LV hypertrophy (in response to volume overload), or mixed concentric/eccentric hypertrophy as may occur following MI (figure 6). (See 'Structural and functional changes' above.)

•Structural remodeling is often associated with molecular events leading to changes in the expression and/or activity of proteins involved in virtually every aspect of myocardial function, including the hemodynamic, energetic, and electrical properties of the heart. (See 'Cellular and molecular changes' above.)

•Factors influencing remodeling include alterations in hemodynamic load in response to myocardial injury, blood pressure, and neurohormonal activation. (See 'Factors influencing cardiac remodeling' above.)

●The hypothesis that remodeling is pathogenically important in HF is supported by the observation that certain therapies (eg, angiotensin converting enzyme inhibitors) that improve survival in patients with HF can slow or reverse certain parameters of cardiac remodeling. (See 'Structural and functional changes' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Jay N Cohn, MD, who contributed to earlier versions of this topic review.