Building a New Heart From Old Parts

Abstract

See related article, pages 1374–1386 The prevailing dogma in cardiac biology for almost a century has been that the adult mammalian heart is a terminally differentiated organ. According to this paradigm, a 100-year-old human heart is comprised of a population of cardiomyocytes that are as old as the individual. Over the last decade, work from the laboratory of Piero Anversa and others has challenged this dogma.1 Cardiac biologists are now confronted with an alternative conceptual framework proposing the heart as a dynamic, self-renewing organ, capable of cardiomyocyte turnover throughout life. Heart disease is the leading cause of death in the developed world. A major reason for this is that the adult mammalian heart has limited regenerative capacity following injury. The default healing response to myocyte loss in the adult mammalian heart (eg, following myocardial infarction) involves replacement of myocytes with fibrous, noncontractile scar tissue. The consequent loss of contractile units compromises cardiac function and ultimately leads to heart failure. Absence of regeneration in the adult mammalian heart contrasts with the impressive regenerative potential of lower vertebrates, such as urodele amphibians and teleost fish, which are capable of regenerating significant portions of ventricular myocardium following injury.2,3 Although studies in adult rodents and humans suggest that some myocyte repopulation occurs after myocardial infarction,4,5 this response is clearly limited and incapable of circumventing large-scale myocyte loss, fibrosis, and ultimately organ failure. Cardiomyocyte loss accompanies aging. The heart undergoes a series of structural and morphological changes during normal aging that are characterized by cardiomyocyte loss (through apoptosis, necrosis, and autophagy) and hypertrophy of remaining viable myocytes, as well as interstitial and perivascular fibrosis.6 Aging also renders the heart more susceptible to major cardiovascular events.6 Therefore, studies investigating the physiological turnover and aging of myocytes are …