Although ventricular remodeling may occur following any form of myocardial injury [20], most of our knowledge has been acquired from the study of remodeling following MI. Acute coronary occlusion in the clinical setting or in the experimental animal leads to loss of myocardial tissue, depression of myocardial function, and hypotension. This causes baroreceptor-mediated activation of a number of neurohormones that help stabilize the hemodynamics through an increase in heart rate, contractility, and fluid retention. However, continuous activation of these mechanisms, designed for short-term support of blood pressure [37], may lead to progressive LV remodeling and dysfunction. Two distinct phases have been identified following MI: early postinfarct LV remodeling and late progressive LV remodeling.

Loss of regional wall function after acute MI results in an abrupt increase in loading conditions of the ventricle that brings on a unique pattern of remodeling involving the infarct area, the border zone, and the remote noninfarcted myocardium. Thinning and stretching of the acutely infarcted myocardium lead to infarct expansion, the first feature of LV remodeling [21, 22]. Although later thinning of the LV wall also occurs in the noninfarcted myocardium, the cellular mechanisms are different in the two regions. In the infarcted myocardium, wall thinning is pronounced and is a result of loss of myocytes, collapse of the intercellular space, and stretching of surviving myocytes [21–23, 38, 39]. This may lead to bulging of the infarct zone that can result in ventricular rupture, aneurysm, mitral insufficiency, and ventricular tachyarrhythmias. In the noninfarcted regions, myocardium thins because of a decrease in the number of myocytes across the wall [38, 39]. Two mechanisms—myocyte slippage [38] and myocyte loss from necrosis [40–42] and apoptosis [41, 43]—have been proposed to explain this decrease.

It has been suggested that “myocyte slippage” plays a major role in progressive chamber dilation leading to failure [8, 38, 44], although much of the literature mentioning this phenomenon is rather vague. This concept usually refers to slippage of myocytes past one another transversely or linear slippage of individual myofibrils within myocytes [44, 45].

Increased myocardial collagenase activity (see discussion under Extracellular Matrix Remodeling below) is believed to disrupt intermyocyte collagen struts, leading to side-to-side slippage of myocytes [46]. Such a process could reduce wall thickness and increase the volume of the ventricle. Linzbach [44] and others [38] have noted reduced numbers of myocytes across the wall as evidence of myocyte slippage. However, this explanation may be too simplistic. For a meaningful discussion of the slippage concept, we need to consider the three-dimensional nature of myocyte-to-myocyte interconnections. Each myocyte is connected to an average of 5–10 neighboring myocytes via end-to-end and side-to-side intercalated disks (◘ Fig. 17.2) [47]. Slippage implies disruption of intercalated disks. Once the disks are disrupted, they may be unable to reconnect, resulting in poorly coordinated contractions.

Early infarct expansion after MI may be followed by progressive ventricular dilatation and dysfunction over subsequent months and years, involving predominantly the noninfarcted segments. The mechanisms responsible for this inexorable deterioration of LV structure and function are not entirely clear but are related to continued activation of neurohormones and cytokines such as norepinephrine, angiotensin II, aldosterone, endothelin, and tumor necrosis factor. These factors, in combination with increased wall stress and mechanical stretch of the myocytes, upregulate a large number of signaling pathways, leading to structural and functional changes in the myocyte and nonmyocyte compartments that underlay a reduction in LV function and the progression of HF. In the discussion that follows, changes in these individual components will be described and their implications discussed .

The remodeling process results in important changes in the cardiac myocytes. These include myocyte hypertrophy, myocyte loss by necrosis [41, 42, 62] and apoptosis [41, 63–66], and changes in the structural proteins with downregulation of contractile and sarcomeric skeleton proteins and upregulation of cytoskeletal and membrane-associated proteins [67]. In addition, loss of myofilaments, nuclear enlargement, development of multiple small mitochondria, decrease in the T-tubular system, and sarcoplasmic reticulum are common histological features of the failing myocardium [68].

Grossman and coworkers proposed that alterations in myocyte shape and size determine the type of cardiac hypertrophy [69]. In conditions with pressure overload such as aortic stenosis or hypertension, parallel addition of sarcomere causes an increase in myocyte cross-sectional area with no increase in myocyte length (◘ Fig. 17.3) [70–72]. This leads to an increase in wall thickness and concentric LV hypertrophy (increase in ratio of wall thickness to chamber dimension) [69, 73]. In conditions with volume overload such as aortic and mitral regurgitation, ventricular volume and wall thickness increase proportionally, and this is associated with a corresponding proportional increase in both myocyte length and cross-sectional area (addition of sarcomeres both in parallel and series) [74] (◘ Fig. 17.3). It appears that during the compensated stage of concentric LV hypertrophy, wall stress does not increase.

After a large MI, progressive LV dilatation is due to an increase in myocyte size which occurs predominantly by laying of sarcomeres in series, resulting in an increase in myocyte length, with only mild increase in width and cross-sectional area [75–78] (◘ Fig. 17.4). This further increases cavity volume with no change or a decrease in wall thickness. Myocyte length is the major determinant of changes in LV size, and most of the increase in LV volume can be explained by an increase in myocyte length [75, 77–79]. Although LV mass increases, the increase in LV volume is proportionately greater, so that mass-to-volume ratio, an important determinant of wall stress, is reduced. The development of myocardial hypertrophy after MI, therefore, results in eccentric hypertrophy (cavity dilation with a decrease in wall thickness to chamber dimension ratio) that increases wall stress.

In volume-overload conditions such as mitral and aortic regurgitation, ventricular hypertrophy remains appropriate and helps to maintain normal wall stress for variable periods of time. Transition from a compensated to a decompensated state is associated with further increase in chamber volume but no increase in wall thickness. This results in a decrease in mass-to-volume ratio and increase in wall stress. The cellular mechanisms responsible for this are not entirely clear, but they could be related to an arrest in growth of the myocytes in the transverse diameter, resulting in myocyte lengthening without further change in myocyte cross-sectional area. Studies of mitral regurgitation in the dog, and in patients at the time of mitral valve surgery, also show a decrease in myocardial myosin content proportional to the degree of LV dysfunction [74, 80]. Thus, reduced contractility in mitral regurgitation could, in part, be due to loss of contractile elements. Although aortic and mitral regurgitation are often considered together as volume-overload conditions, the two have their specific pathophysiologic features .

In aortic regurgitation, the sum of the regurgitant and forward stroke volume is ejected into the aorta in systole, resulting in a wide pulse pressure and systolic hypertension. Therefore, aortic regurgitation creates both volume and pressure overload on the left ventricle. Systolic wall stress is always higher in aortic regurgitation than in mitral regurgitation [81] and is often as high as in aortic stenosis (the classic pressure-overload condition) [82]. These different loading conditions in mitral and aortic regurgitation create two different types of ventricular geometry. In mitral regurgitation, there is an enlarged thin-walled left ventricle in which the mass-to-volume ratio is less than 1.0 [83]. In contrast, in aortic regurgitation, the mass-to-volume ratio is normal at 1.0 [84]. Whether the cellular hypertrophy at the onset of failure is different in these two conditions remains to be determined.

In pressure-overload conditions, concentric ventricular hypertrophy (thick wall, normal chamber volume, and high mass-to-volume ratio) helps to keep wall stress normal despite high ventricular pressure. Because systolic stress (afterload) is a major determinant of ejection performance, the normalization of systolic stress helps to maintain a normal stroke volume despite the need to generate high levels of systolic pressure [12]. Transition to failure is accompanied by progressive cavity enlargement and decline in the mass-to-volume ratio, resulting in eccentric ventricular hypertrophy. In spontaneously hypertensive rats, transition to failure is preceded by myocyte lengthening without an increase in myocyte cross-sectional area [70, 71].

Cell death is an important determinant of progressive cardiac remodeling and LV wall thinning. A reduction of contractile material is a prominent feature in HF, and myocyte loss may occur either by necrosis or apoptosis [41].

Myocyte necrosis : Necrosis generally occurs in the setting of catastrophic events such as MI or inflammation and is characterized by severe membrane alterations, release of cell breakdown products, and polymorphonuclear infiltration. However, slow myocyte loss by necrosis is also a common feature of chronic HF [40–42, 85]. During the progression of HF, activation of several neurohormones occurs, including norepinephrine, angiotensin II, and endothelin. These neurohormones are directly toxic to the myocardium and have been shown to cause myocyte necrosis in various animal models [86, 87]. Moreover, in patients with severe HF, circulating levels of troponin are often increased, suggesting ongoing myocyte necrosis [88, 89]. Myocyte loss through necrosis probably contributes to progressive LV dilatation and wall thinning. Even very low plasma concentrations of troponin are predictive of adverse outcomes in patients with chronic HF [88].

Myocyte apoptosis : Apoptosis or programmed cell death is an evolutionarily conserved process of cell death, wherein cells die without provoking significant inflammatory response. Evidence shows that apoptosis contributes to the progression of HF. Apoptosis occurs through a cascade of subcellular events including cytochrome c release into the cytoplasm and activation of proteolytic caspases [90]. Activated caspases lead to fragmentation of cytoplasmic proteins, including contractile apparatus [91]. Caspase-3 (the final executioner in the apoptotic cascade) overexpression or activation has been shown to directly reduce the contractile performance of the LV [92]. The degree of myosin cleavage with caspases correlated with the contractile performance of the heart [93]. It has been proposed that the release of cytochrome c from mitochondria and contractile protein loss in living heart muscle cells contributes to systolic dysfunction [90]. Apoptosis is involved at multiple points in the natural history of HF. This includes initial events like ischemia, infarction, and inflammation as well as those events occurring later in established LV dysfunction. Several of the factors implicated in the pathogenesis of HF such as myocardial stretch [94], norepinephrine [95], angiotensin II [96, 97], tumor necrosis factor-α (TNF-α), and oxidative stress [98, 99] may provoke apoptosis.

While the presence of myocardial apoptosis has been confirmed in end-stage human HF [65, 66] and in several animal models [41, 43, 63, 64], questions remain whether apoptosis is a cause or a consequence of HF. Myocyte apoptosis may be a factor in the transition from compensated to uncompensated HF [91]. This has been shown in several animal models of experimentally induced LV hypertrophy and HF [100–102]. Several studies have demonstrated the presence of apoptosis late after MI [103–105].

The complexity of events involved in the pathogenesis of ventricular remodeling cannot be solely attributed to myocyte hypertrophy and cell loss. The hypertrophied myocytes in the remodeled failing heart also show alterations in most of the structural proteins (◘ Table 17.1) [67]. Following is a brief description of the structural protein (◘ Fig. 17.5), alterations that occur in HF proteins, and their functional consequences.

Apart from the myocyte compartment, the chronically failing heart is characterized by iterations in the extracellular matrix (ECM), particularly by fibrous tissue formation [62]. Such an adverse accumulation of ECM raises myocardial stiffness and impairs contractile behavior [134].

The mechanical effects of LV remodeling set in motion several self-sustaining deleterious consequences. As the ventricle enlarges, LV geometry alters from a normal prolate ellipse to a mechanically disadvantageous spherical or globular shape. The result is an increase in meridional wall stress [161], abnormal distribution of fiber shortening, increase in oxygen consumption [161, 162], and abnormal myocardial bioenergetics [163]. The spherical shape of the LV leads to dilatation of the atrioventricular ring and stretching of the papillary muscles, resulting in functional mitral regurgitation [164], which contributes to a further decrease in forward cardiac output. Moreover, the high LV end-diastolic volume and pressure promote subendocardial ischemia that aggravates LV dysfunction and neurohormonal activation, decreases exercise capacity [165], and increases the risk of ventricular arrhythmias [166].

A fundamental question that must be addressed before embarking on a strategy to reverse hypertrophic and structural myocardial remodeling is whether remodeling is good or bad. Distinction is often made between a compensatory (adaptive) and a maladaptive process. An adaptive component enables the heart to maintain function in response to pressure or volume overloading in the acute phase of cardiac injury [167]. Acute distension of the viable myocardium and the operation of the Frank-Starling mechanism through an increase in sarcomere length are, therefore, entirely appropriate beneficial responses. Likewise, augmentation of chronotropic and inotropic activity through adrenergic receptor stimulation that tends to maintain pump function during the abrupt loss of contractile tissue can be considered compensatory.

Progressive LV dilatation after MI can also help to maintain stroke volume in the face of reduced contractile function and has been considered an adaptive and compensatory response [3, 168]. Under these circumstances, however, increased LV volume is not due to sarcomere stretch, but because of the addition of new sarcomeres in series [78]. Therefore, it is not a mechanism of enhancing contractility on the basis of Frank-Starling mechanism. Such a progressive remodeling and LV dilation does not normalize, but increases wall stress and is associated with a poor prognosis [19, 168].

Moreover, the prevention of very early LV dilation with the use of angiotensin-converting enzyme (ACE) inhibitors and beta-blockers does not have any deleterious hemodynamic consequence [169–171]. Indeed, Sharpe et al. [169] have demonstrated that the attenuation of LV remodeling with early initiation of ACE inhibitors is associated with a greater increase in stroke volume as compared with a placebo. Furthermore, the prevention of remodeling by early initiation of an ACE inhibitor or beta-blocker, after MI, in selected populations with LV dysfunction [31, 34] and even in unselected populations [172] is associated with significant reduction in mortality and morbidity [34, 170, 173, 174]. Hence, ventricular remodeling and dilation after MI may be maladaptive from the very start and should be a target for aggressive antiremodeling therapy .

In contrast, an increase in ventricular mass that helps to normalize wall stress in aortic stenosis and hypertension may be an appropriate compensatory response. Because systolic stress (afterload) is a major determinant of ejection performance, normalization of systolic stress helps to maintain a normal EF while generating high levels of systolic pressure [12]. However, LV hypertrophy has been shown to be an important independent risk factor for mortality and morbidity [17]. Similarly, a proportional increase in chamber volume, wall thickness, and mass in mitral and aortic regurgitation normalizes wall stress and is an obligatory response to maintain a large stroke volume that is necessitated by the regurgitant volume. Until the initial volume and pressure overload is matched by adequate hypertrophy, the process may be considered adaptive and compensatory. Eventually, a mismatch occurs with progressive dilation and the process becomes maladaptive and decompensatory, and HF becomes clinically manifest [175, 176]. There is no data to indicate when the transition from possible adaptive to maladaptive remodeling occurs; such a transition and its time course can vary greatly. However, once established beyond a certain phase, remodeling likely contributes to progression of HF. Thus, whether remodeling is beneficial or deleterious cannot be viewed as a stereotypical process. Today’s challenge is taking advantage of the adaptive features of the hypertrophic response while eliminating or at least minimizing the maladaptive consequences.

“Reverse remodeling” is a concept, where progressive LV dilatation and deterioration in contractile function are not simply arrested, but partially reversed. Two important questions related to reverse remodeling are: “Do myocytes have the ability to remove sarcomeres?” and “Is there any time line beyond which reverse remodeling cannot be achieved?”

Surgical and pharmacological experiments have confirmed that the regression of myocyte hypertrophy with removal of sarcomeres is possible. But insufficient data exist to address the second question. Remodeling is believed to be reversible early in the natural transition from hypertrophy to failure, whereas later, with the development of extensive fibrosis, accumulation of cytoskeletal proteins, and loss of the contractile filaments, an irreversible process sets in [111]. Several therapeutic approaches for HF have been shown to halt or even reverse the remodeling process.