Ventricular remodeling is the process by which heart size, shape, and function are regulated by the interaction of biomechanical, neurohormonal, local trophic, and genetic factors. It is a dynamic interaction of molecular, cellular, and organ-level processes. Ventricular remodeling may be physiological during normal growth and pregnancy, or pathological as in chronic pressure or volume overload from hypertension, valvular, and congenital heart disease—especially in transposition with ventricular inversion, from genetically programmed primary cardiomyopathies and most commonly following acute ischemic cardiac injury. If unchecked, remodeling can result in molecular maladaptations, cellular dysfunction, reorganization of the extracellular matrix, and vascular changes that culminate in progressive dilatation, interstitial fibrosis, increased myocardial stiffness, chamber distortion, and heart failure. The initial biological trigger for ventricular dilatation varies but most frequently it is acute infarction following which the injured myocardium stops contracting with concomitant stretching and thinning of the infarct zone. This combination increases wall stress, which is the patho-etiological mechanism that drives the remodeling process and triggers the stretch-induced changes in the extracellular matrix that begin the process of infarct repair. As the heart remodels, LV geometry changes from a prolate ellipse to a more spherical shape.^7,8 These changes in chamber shape are accompanied by increase in ventricular volume and mass, and alteration in the equilibrium between collagen deposition and degradation. Increasing the myocardial collagen content during repair changes the material properties of the myocardium, resulting in increased chamber stiffness. Alteration in left ventricular composition, architecture, and stiffness affect LV filling dynamics, rate of cross-bridge formation, and sarcoplasmic sequestration of cytosolic calcium that impact upon systolic as well as diastolic function. Progressive increase in LV volume is associated with deterioration in LV performance and a poor clinical outcome.⁹ Functional mitral regurgitation (MR) is ubiquitous during LV remodeling because of an imbalance between tethering forces—annular dilatation, disruption of the mitral valve and subvalve apparatus, increased LV sphericity and LV dilatation —versus closing forces—reduction of LV contractility, global and regional LV dyssynchrony, papillary muscle asynchrony, and altered mitral systolic annular contraction.¹⁰ Functional MR is typically dynamic and exacerbated during exercise. Increase in MR during exercise identifies a subgroup of patients at particularly high risk for adverse cardiovascular events.¹¹ Development of MR is important because it results in an
additional volume overload to an already severely dysfunctional LV that often escalates the deterioration of LV function and the early onset of failure.

In the normal heart the electrical pacemaker impulse is initiated by the sinus node and conducted rapidly via specialized Purkinje network in such a temporal and spatial distribution as to activate synchronous mechanical ventricular contraction within 40 ms. Mechanical contraction begins earlier at the apex and then a wavefront of electrical depolarization spreads to the base of the heart, resulting in concentric inward wall motion during ventricular emptying and similar temporally coordinated outward wall motion during relaxation and diastolic filling. Left ventricular dyssynchrony in the broadest terms is when there is heterogeneity of systolic contraction, that is, when some regions of the myocardium are contracting early and some are contracting late, typically resulting from a delay in activation of the lateral LV free wall resulting in prolongation of the QRS duration >120 ms on the surface electrocardiogram. Dyssynchrony compromises mechanical efficiency, with transmission of the ventricular blood pool between two intracavitary sinks (the stretched lateral wall in early systole and the anteroseptal region in late systole). Functional MR may further aggravate this “intracavity” volume overload. Dyssynchrony also causes changes in regional hypertrophy, blood flow, and oxygen consumption, resulting in local alterations in myocardial protein expression.¹² (Table 7.1)

Pharmacologic therapies for chronic, advanced heart failure include β-adrenergic receptor blocking agents, angiotensin converting enzyme inhibitors/angiotensin receptor blockers that attenuate LV remodeling but with rare exception do not reverse LV remodeling. However, their use is the accepted standard of care and is associated with improved survival, enhanced exercise capacity, decreased adverse cardiovascular events, and symptomatic relief. Traditional surgical therapies including myocardial revascularization, correction of mitral regurgitation by valve repair or replacement, ventricular volume reduction, and epicardial restraint devices have all aimed at reducing LV loading conditions but have not achieved LV reverse remodeling long term. Occasionally obligate use of a left ventricular assist device (LVAD) has resulted in reverse remodeling such that the LVAD has been removed with sustained recovery of LV function.

The current goal of heart failure therapy is not simply to attenuate, but to reverse the remodeling process. Reverse remodeling involves reduction in LV size, near-normalization of LV architecture, increase in contractile function, and accompanying symptomatic benefit. Reduction of volumes is often but not always accompanied by a reversal of the deranged molecular processes. Clinical and experimental data are still limited regarding the correlation between macroscopic and molecular remodeling.¹³ Reverse remodeling is accompanied by improved survival, exercise capacity, and quality of life.

LV remodeling and reverse remodeling have been assessed echocardiographically in the randomized CRT trials either as changes in linear LV cavity dimensions, wall thickness, end diastolic and systolic LV volumes, ejection fraction, sphericity index,¹⁴ LV mass, and severity of mitral regurgitation. Assessment of LV volumes and ejection fraction are important because they are powerful predictors of long-term mortality and adverse cardiovascular events.^15,16 More recently tissue Doppler imaging (TDI) has been used prior to CRT to detect dyssynchrony in patients likely to benefit from CRT and also post CRT to demonstrate improvement in the synchrony of regional LV contraction from baseline values. A few studies have attempted to characterize remodeling associated with CRT using 3-dimensional (3D) echocardiographic imaging.¹⁷ Three-dimensional echocardiographic techniques currently available enable comprehensive characterization of right ventricular size, shape, function, degree of dyssynchrony, and extent of RV remodeling in heart failure at baseline and after CRT. Thus, structural RV remodeling can be correlated with improvement in symptoms following CRT.