Their latest research reveals that impaired energy production in heart muscle may underlie heart failure in some hypertensive patients. The researchers assert that a molecular factor involved in maintaining the heart's energy supply could become a key to new approaches to prevent or treat heart failure.
The molecular factor, a protein called estrogen-related receptor alpha (ERR alpha), helps the heart keep up with energy-draining conditions like high blood pressure, which makes the heart work harder to pump blood.
In the July issue of Cell Metabolism, Kelly and his colleagues report that mice born without any ERR alpha developed symptoms of heart failure when their hearts were forced to pump against high pressure. The hearts of normal mice took that pressure overload in stride and stayed healthy. Those contrasting outcomes suggest that heart health greatly depends on ERR alpha.
'The stress of a cardiac pressure overload asks heart muscle to manufacture more high energy compounds, and without ERR alpha, they can't do it,' explains Kelly, the Tobias and Hortense Lewin Professor and Chief of the Cardiovascular Division. 'You could say that in high blood pressure conditions, the heart fails because it becomes energy starved. And if you could feed the heart — by using a drug that enhances ERR, for example — you might enable the heart to better keep pace with its energy requirements.'
Although preventions and treatments are now available for heart failure due to high blood pressure, almost all of those drugs act outside the heart by dilating blood vessels throughout the body to reduce resistance.
In the future, doctors might look for diminished energy capacity in the hearts of hypertensive patients and administer drugs that would rev up energy-producing pathways such as those controlled by ERR alpha, according to Kelly. Kelly is also director of the Center for Cardiovascular Research and professor of medicine, of pediatrics and of molecular biology and pharmacology.
ERR alpha sits in the nucleus of cells and senses how much energy is needed. When a heart cell finds itself short on energy, say because it's being called on to contract harder or faster, its ERR is activated by an inducible co-activator called PGC-1, turning on genes that increase the heart's capacity to burn fats for fuel.
In mice that lacked ERR alpha and that were exposed to pressure overload, the researchers observed signs of early heart failure: the mouse hearts dilated and didn't contract effectively, the heart walls thinned, fibrous connective tissue accumulated and some heart cells died. They also saw that the hearts had depleted fuel reserves.
Kelly indicates that these studies show for the first time that changes in the ability of the heart to produce energy lead to heart failure in some cases. 'ERR and some of its partners in the cell are a little like puppeteers controlling the expression of genes for energy production,' Kelly says. This research is especially exciting because ERR can be activated with small compounds, making it a good target for drugs.