However, what if the outcome of the treatment was profoundly different in humans when compared with mice? Are we failing to consider the critical differences between mouse and man? Two studies published in the March 14 issue of the Journal of Clinical Investigation led by Evangelia Kranias and researchers at the University of Cincinnati reveal that a mutation in the human gene encoding the protein phospholamban (PLN) is linked to heart failure. In striking contrast to previous reports that indicate that "knock-out" or inhibition of PLN is beneficial in mouse models of heart failure, the researchers reveal that humans with mutated forms of PLN develop lethal heart failure.
Heart failure is a leading cause of human morbidity and mortality worldwide and costs close to $18 billion in health-carerelated costs in America each year. Characterized by suppressed calcium cycling in the heart, it impairs the ability of the heart to supply adequate oxygen- and nutrient-rich blood to the body. Calcium regulates the contraction and relaxation of heart muscle and PLN acts to halt calcium cycling at the end of the contraction so that muscles may relax between beats.
Recent experimental successes in mice have generated much enthusiasm for treating an array of conditions that ultimately result in heart failure by "knocking-out" the PLN gene and thereby enhancing calcium cycling.
However, the effect of inhibiting PLN in cases of cardiac hypertrophy (which can progress to heart failure) was unknown.