Introduction

The Big Heart Disease Lie

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The heart is an organ whose function that hinges critically on its supply of and demand for oxygen. supply of oxygen to the myocardium is influenced by factors such as blood oxygen content, blood pressure, coronary arterial resistance, and maximal coronary flow reserve. The last is considered the most important factor and is defined as the ratio of maximal achievable myocar-dial blood flow rate, by pharmacological selective coronary vessel dilation, to basal myocardial blood flow rate. Demand for oxygen by the myocardium is governed by factors such as heart rate, heart wall tension, wall thickness, and contractile state of heart muscle cells (cardiomyocytes).

In the face of stresses that significantly disturb the balance of oxygen supply and demand in the heart, the left ventricle of the heart in particular is known to undergo compensatory structural remodeling. The left ventricle is responsible for pumping blood systemically through the tissue of organs and, as such, is considered key among the four heart chambers. A common clinical complication experienced by the left ventricle is myo-cardial infarction (more commonly known as a heart attack) in which a segment of the left ventricular myocardium is damaged by a local deficiency in oxygen supply. Subsequently, the damaged chamber cannot generate adequate mechanical forces, a situation that then causes the surrounding myocardia to attempt to compensate with an increase in muscle mass. From a cellular perspective, this increase occurs by expanding the size of exist ing cardiomyocytes (termed hypertrophy) as opposed to generating additional cells (termed hyperplasia).

Cardiomyocytes can be damaged or killed by: (1) disrupting their supply of oxygenated blood and (2) overworking them by increasing the demand for work beyond normal limits. Within an area directly affected by myocardial infarction, the dead cardiomyocytes are replaced by fibroblasts, which are incapable of doing cardiac work. In areas outside the infarction, the cardiomyocytes may undergo compensatory hypertrophy. A functionally stable degree of left ventricular hypertrophy is only considered to be temporary, and subsequent compensatory hypertrophy typically overshoots resulting in overgrown cardiomyocytes.

From a clinical perspective, the sequelae of myocardial infarction commonly include progressive myocardial dysfunction and subsequent congestive heart failure. Customarily, congestive heart failure has been considered an end-stage irreversible clinical condition for which conventional medical management is primarily intended to relieve symptoms and slow deterioration. Thus, this treatment merely accommodates damaged myocardium instead of effecting direct repair to restore normal structure and function.

The experimental therapy known as cell transplantation (or cellular cardiomyoplasty) is intended to achieve repair and regeneration of damaged heart muscle. This approach is directed toward transcending the dogma that the heart and its cardiomyocytes are terminally differentiated and incapable of regeneration. Relatively recent studies have shown that the adult

Damaged Muscle Cellular

Fig. 1. Schematic of cell transplantation in action. In this example, mouse adult stem cells are delivered to a damaged region of the myocardium by intramyocardial injection to effect tissue repair. The mechanisms of repair are unclear, but could include regeneration of cardiomyocytes, vascular cells, or components of the extracellular matrix. © 2001 Terese Winslow.

Fig. 1. Schematic of cell transplantation in action. In this example, mouse adult stem cells are delivered to a damaged region of the myocardium by intramyocardial injection to effect tissue repair. The mechanisms of repair are unclear, but could include regeneration of cardiomyocytes, vascular cells, or components of the extracellular matrix. © 2001 Terese Winslow.

human heart is actually capable of cardiomyocyte regeneration by a number of mechanisms.

Some suggest that regeneration occurs by the proliferation (i.e., hyperplasia) of existing cardiomyocytes (1-4). Others have suggested that the presence of extracardiac stem cells, when introduced to the myocardium, spawn both myocytes and vascular cells through a process termed transdifferentiation or plasticity (5-8). Others have proposed that intracardiac stem cells exist that might partly function by fusing with existing cardiomyocytes in a process termed cell fusion (9,10).

Nevertheless, in the face of myocardial infarction, the human heart typically elicits little or no regenerative response adequately sufficient for innate cardiac regeneration. Thus, the current major strategy of cell transplantation is to amplify such processes to therapeutic levels.

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