Metabolism in heart tissue is disrupted in a number of ways in patients with heart failure. Researchers here followed up on the suspicion that fat metabolism is important in this context. They attempt a genetic modification in mice that compensates for just one of the observed changes in how heart tissue manages (or perhaps mismanages) the adaptation to increased stress, namely the much reduced levels of acyl-CoA. They find that this helps. This may or may not lead to a compensatory therapy that strives to make the end stage disease state less terrible, something that I've always thought is a less desirable development strategy, comparing unfavorably to attempts to repair the underlying causes of the condition. It may, however, have more significance as an assessment of the degree to which metabolic disruption of this nature is important in the progression of heart failure.
Before any physical signs or symptoms of heart failure are present, the first maladaptive changes occur in cardiac cell metabolism - how the heart fuels itself to pump blood through the body constantly. Our hearts burn fuel, much like combustion engines in cars. Instead of gasoline, our heart cells burn fats and a small amount of glucose. When our hearts become chronically stressed, they try to adapt, but some of those changes make things worse.
Researchers examined both mouse models of heart failure and human heart tissue obtained from heart failure patients before and after heart assist devices were surgically implanted. They found that the amount of a reactive fat compound, called acyl-CoA, is nearly 60 percent lower in failing hearts compared to normal hearts. This disruption in the heart's normal metabolism creates toxic fats that impair the heart's ability to function and pump properly. Then the team tested mice that overexpressed a gene for a protein called ACSL1, that's known to make acyl-CoA. When exposed to conditions that cause heart failure, the mice kept making normal amounts of acyl-CoA and the extent of heart failure was reduced and delayed.
By maintaining this fat compound, acyl-CoA, the hearts retained their ability to burn fat and generate energy. Importantly, overexpression of ACSL1 also reduced toxic fats, normalized cell function, and reduced the progressive loss of function in the enlarged mouse hearts. When the team examined failing human hearts that had the help of a left ventricular assist device (LVAD), they found similar effects - the levels of acyl-CoA had restored to normal when the sick hearts didn't have to work beyond their capacity. "This tells us there's an important relationship between fat metabolism in the heart and the inability to pump well, and we need to learn more. We believe targeting the normalization of acyl-CoA is a new approach to explore." Next, the team wants to explore how normalizing acyl-CoA helps reduce toxic fats and increase protective fats inside the heart. Soon, they hope to use advanced imaging to track fat metabolism and function in patients' hearts.