The genetics of cardiomyocyte polyploidy.

The regulation of ploidy in cardiomyocytes is a complex and tightly regulated aspect of cardiac development and function. Cardiomyocyte ploidy can range from diploid (2N) to 8N or even 16N, and these states change during key stages of development and disease progression. Polyploidization has been associated with cellular hypertrophy to support normal growth of the heart, increased contractile capacity, and improved stress tolerance in the heart. Conversely, alterations to ploidy also occur during cardiac pathogenesis of diseases, such as ischemic and non-ischemic heart failure and arrhythmia. Therefore, understanding which genes control and modulate cardiomyocyte ploidy may provide mechanistic insight underlying cardiac growth, regeneration, and disease. This chapter summarizes the current knowledge regarding the genes involved in the regulation of cardiomyocyte ploidy. We discuss genes that have been directly tested for their role in cardiomyocyte polyploidization, as well as methodologies used to identify ploidy alterations. These genes encode cell cycle regulators, transcription factors, metabolic proteins, nuclear scaffolding, and components of the sarcomere, among others. The general physiological and pathological phenotypes in the heart associated with the genetic manipulations described, and how they coincide with the respective cardiomyocyte ploidy alterations, are further discussed in this chapter. In addition to being candidates for genetic-based therapies for various cardiac maladies, these genes and their functions provide insightful evidence regarding the purpose of widespread polyploidization in cardiomyocytes.