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Getting to the Heart of  Size

heart

The fact that heart muscle cells retain the ability to divide, at least until adolescence, opens the way to new approaches for heart repair and the treatment of heart disease.

By Amy Nicks, Bob Graham, Nawazish Naqvi, Ahsan Husain, Ming Li & Siiri Iismaa

The discovery that cardiac muscle cells can divide until adolescence opens the way to new approaches to treating heart disease.

The mammalian heart undergoes a remarkable four-fold increase in size between birth and adolescence. For more than a century this growth has been thought to be only achieved by the enlargement of the heart muscle cells.

However, our research in mice has revealed that at a predetermined point after birth and just prior to adolescence there is a burst of cell division triggered by a surge in thyroid hormone. The fact that heart muscle cells retain the ability to divide, at least until adolescence, opens the way to new approaches for heart repair and the treatment of heart disease.

Heart Development after Birth

The heart is one of the most important organs in the body, pumping blood that delivers oxygen and nutrients to the entire body. To do this effectively during the period from birth to adolescence it is essential that heart growth keeps up with the rapid increase in body size and blood volume at this time. Indeed, during this period there is a fourfold increase in heart size. How is the extraordinary quadrupling of heart size during this critical period of development achieved?

For more than a century it was thought that heart muscle cells, which account for 80% of the heart’s weight, stop dividing shortly after birth and that subsequent heart growth is achieved entirely by an increase in the size of these cells – a process called hypertrophy. But by carefully counting the number of heart muscle cells in mice and looking for signs that these cells are dividing over 24-hour periods, we have found that heart growth involves not only hypertrophy of heart muscle cells but also the addition of half a million new cells. In research published in Cell this year we found that these cells retain the ability to divide until long after birth and can thus produce new cells from existing heart muscle cells.

The addition of new cells to the heart occurs during a precisely timed 24-hour period 15 days after birth (postnatal day 15; P15), just before the start of adolescence in mice. This discovery overturns 100-year old dogma that heart muscle cells become quiescent soon after birth, losing their ability to divide and make more cells. Our discovery opens up opportunities to treat heart disease in a way not previously thought possible.

Response of the Developing Heart to Injury

If heart muscle cells cannot divide, this would severely limit the heart’s response to stress and injury. It would only be able to heal through scar formation, which impairs heart function. Other organs, such as the liver, skin and the lining of the gut, can regenerate after injury, completely restoring both the structure and function of these tissues.

However, the finding that heart muscle cells can still divide until adolescence opens a window of opportunity for treating heart disease, especially those present at birth. In support of this idea, we showed that in the preadolescent period when heart muscle cells can still divide, repair of hearts in response to injury is better than in adult animals whose heart muscle cells have already lost their ability to divide.

Cell Division in Heart Muscle

Shortly after birth, the majority of heart muscle cells divide and in some mammals become binucleated or multinucleated (i.e. the nucleus divides to leave two or four nuclei in one cell). Indeed, the majority of heart muscle cells in rodents are binucleated by 5–7 days after birth (P7). It used to be believed that once cells became bi- or multinucleated that they were no longer able to divide. So how did we find that heart muscle cells can still divide long after birth?

We actually found that, again contrary to dogma, the formation of half a million new heart muscle cells results from the division of mostly binucleated heart muscle cells. Moreover, this proliferative burst was accompanied by significant increases in the expression of several key genes that are required for cells to re-enter the cell cycle and divide. Consistent with this process of cell division, the new daughter cells thus formed (whether mononucleated or binucleated) were significantly smaller than their “parental” cells.

Thus, multiple lines of evidence are consistent with the idea that heart muscle cells, predominantly binuclear cells, can and do divide long after birth.

Nature has been very clever in managing this impressive heart growth at P15. While an initial burst of cell division occurs uniformly throughout the heart during P1–P4, we have observed that heart muscle cell proliferation only occurs at P15 in the inner subendocardial zone of the left ventricle. This is the high pressure chamber of the heart. During contraction, the stress in the wall of the left ventricle is highest in the sub­endocardial zone. Wall stress is known to stimulate heart muscle cell division.

Thyroid Hormone Triggers Heart Growth

Curiously, the increase in heart weight during the period from birth to adolescence is greater than the increase in body weight for a short period during P10–P17. This cannot be fully explained by an increase in circulatory demand, as this is proportionate to body growth.

The initial phase of this disproportionate increase in heart weight involves enlargement of heart muscle cells that predominantly results from a lengthening of these cells, as well as an increase in the expression of the contractile protein a-myosin heavy chain. These responses are characteristic of the changes observed in the heart when thyroid hormone levels are increased. It was therefore interesting when we found that circulating levels of the thyroid hormone T3 increased approximately sixfold between P10–P12.

To test whether T3 is required for heart growth we used an inhibitor that lowered T3 levels by 43%. This prevented not only the increased expression of heart muscle cell genes but also the increase in heart weight that occurs during this period.

Therefore, together with an increase in left ventricular wall stress, T3 critically regulates the ratio of heart-to-body weight and drives a rapid increase in heart size during early pre-adolescence. Specifically, T3 activates a biochemical pathway in the nucleus of heart muscle cells that stimulates cell proliferation. Given this effect of T3, treatment of heart diseases with thyroid hormone or thyroid hormone-type drugs may be useful for stimulating heart muscle cells to divide, thus allowing proper repair of the heart after injury.

In summary, we have shown for the first time that the ability of heart muscle cells to divide persists long after birth. This allows the profound increase in heart size and function that is required to meet the demands of the rapid growth of the body during the period between birth and adolescence. These findings, if replicated in humans, hold promise for the complete structural and functional repair of injured or diseased hearts, which remain major causes of morbidity and mortality in both developed and underdeveloped countries.

Amy Nicks is a PhD student at the University of Leeds, and took part in this research at the Victor Chang Cardiac Research Institute (VCCRI) with Bob Graham (Executive Director of VCCRI and Des Renford Professor of Medicine at The University of NSW), Nawazish Naqvi and Ahsan Husain (Emory University), and Ming Li and Siiri Iismaa (VCCRI).