Adverse Remodeling

Heart failure is a clinical syndrome defined by signs and symptoms. Heart failure can have many different causes and manifestations. New technologies have revealed important insights into the underlying disease processes. These insights make it possible to develop new treatments that address the underlying causes and disease processes. Adverse or maladaptive remodeling is one such important underlying disease process.

The easiest way to describe the process of adverse remodeling is following an acute period of cardiac ischemia, such as a heart attack. Following the heart attack, the injured area shows inflammation and tissue repair resulting in scar formation. In most cases this is where it ends. However in some patients, after healing of the damaged area of the heart muscle, the scarring process continues beyond the injured area. In these patients, all of the left ventricle can be affected by changes to the extracellular matrix—the space around the heart muscle cells. In effect, the process that aimed to heal the injured area progresses beyond the edges of the injury and spreads throughout the heart muscle. This is a disease process defined by a distinct biochemical mechanism. As we currently understand it, this disease process is mediated galectin-3. Galectin-3-mediated means that the presence of galectin-3 in the heart tissue is required for the disease process. It also implies that blockade of galectin-3 will prevent the development or slow the progression of this particular form of heart failure. Our understanding of the role of galectin-3 in adverse remodeling has come from preclinical and clinical studies. In animal experiments, administration of galectin-3 to the heart resulted in adverse remodeling with diffuse cardiac fibrosis and stiffening. In these animal studies, adverse remodeling reduced the heart’s ability to pump normally, causing heart failure.

The understanding of galectin-3-mediated adverse remodeling continues to evolve. The term “heart failure” encompasses a wide variety of forms, including the galectin-3-mediated form. Adverse remodeling is a term that is often used to describe this progressive fibrotic cardiac disease. Adverse remodeling may occur in the absence of overt cardiac injury or alterations in cardiac loading conditions. This disease process is a clinically significant problem that can lead to left ventricular dilatation and dysfunction, and progression to heart failure. As with many other medical terms, there is no common definition of adverse remodeling. Many experts use this term for the progressive fibrotic changes in the extracellular matrix area following myocardial injury and some use it more as a term that relates to structural changes, for example, as can be seen when the heart is imaged by echocardiography or magnetic resonance imaging (MR).

Adverse remodeling and the development of galectin-3-mediated heart failure does not appear to require a prior heart attack for its initiation. In addition to a symptomatic heart attack and or other acute coronary syndromes, many forms of cardiac injury remain unnoticed and undiagnosed. Some patients who suffer subclinical myocardial injury may develop galectin-3-mediated fibrosis and adverse remodeling.

Step-by-step biology of galectin-3

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Figure 1: Myocardial infarction (MI) triggers inflammatory and wound-healing response. Figure 2: Macrophages carrying galectin-3 infiltrate necrotic tissue. Figure 3: Macrophages release galectin-3.
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Figure 4: Galectin-3 binds and activates the myofibroblast, leading to collagen synthesis. Figure 5: Collagen deposition leads to scar formation. Figure 6: Cardiac remodeling and dilatation develop.

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Further Reading

  1. Cohn JN, 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.
  2. de Boer RA, Yu L, van Veldhuisen DJ. Galectin-3 in cardiac remodeling and heart failure Curr Heart Fail Rep. 2010;7:1-8.
  3. deFilippi CR, Felker GM. Galectin-3 in heart failure-linking fibrosis, remodeling, and progression US Cardiology. 2010;7:67-70.
  4. Lambert JM, Lopez EF, Lindsey ML. Macrophage roles following myocardial infarction. Int J Cardiol. 2008;130:147-58.
  5. Opie LH, Commerford PJ, Gersh BJ, et al. Controversies in ventricular remodelling Lancet. 2006;367:356-67.
  6. Sharma UC, Pokharel S, Van Brakel TJ, et al. Galectin-3 marks activated macrophages in failure-prone hypertrophied hearts and contributes to cardiac dysfunction Circulation. 2004;110:3121-28.
  7. Spinale FG. Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function Physiol Rev. 2007;87:1285-342.

For a complete list of related readings, please see our Bibliography.